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A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly
A cross-over medication trial for patients with autosomal dominant hypertension with brachydactyly. We examined a family with autosomal-dominant hypertension and brachydactyly from northeastern Turkey. The hypertension was defined as severe, resulting in stroke before age 50 years, featuring normal renin, aldosterone, and catecholamine responses, and did not appear to be salt-sensitive. The responsible gene resides on chromosome 12p. To determine
Herbert Schuster; Okan Toka; Hakan R Toka; Andreas Busjahn; Özgür Öztekin; Thomas F Wienker; Nihat Bilginturan; Sylvia Bähring; Falko Skrabal; Hermann Haller; Friedrich C Luft
Absence of hypertensive retinopathy in a Turkish kindred with autosomal dominant hypertension and brachydactyly
BACKGROUND—A 60 member Turkish kindred with autosomal dominant hypertension, which cosegregates completely with brachydactyly and short stature, was studied. Affected people have severe hypertension and generally die of stroke by the age of 50. The hypertension closely resembles essential hypertension and, accordingly, the mechanisms of blood pressure elevation are unknown. The gene responsible was mapped to chromosome 12p.?METHODS—All 29 affected family members underwent a basic physical examination and funduscopy. Other than markedly elevated blood pressures and the residua of stroke in a few subjects, the apparent lack of end organ damage was striking, including the normal appearing fundi. Five affected individuals were studied in a clinical research unit study. All underwent a complete ophthalmological examination. Fluorescein angiograms were obtained in three subjects.?RESULTS—Systolic blood pressures ranged from 170 to 250 mm Hg, while diastolic blood pressures ranged from 100 to 150 mm Hg in affected individuals. In all affected subjects, the fundi were only minimally altered or clinically normal. All three fluorescein angiograms were normal. Despite severe hypertension since childhood the patients showed no signs of hypertensive retinopathy.?CONCLUSIONS—The absence of hypertensive retinopathy in this novel form of inherited hypertension is due to an altered structure of retinal arteriolar walls or some other protective mechanism. Since evidence of end organ damage is scarce in other organs as well, the protective mechanism appears to be generalised.?? Keywords: hypertension; retinopathy; genetics; fundus, fluorescein angiography
Hattenbach, L.; Toka, H.; Toka, O.; Schuster, H.; Luft, F.
Brachydactyly ("short digits") is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. The various types of isolated brachydactyly are rare, except for types A3 and D. Brachydactyly can occur either as an isolated malformation or as a part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism. For the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrtance. Diagnosis is clinical, anthropometric and radiological. Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known. The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms. There is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function. Prognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.
Temtamy, Samia A; Aglan, Mona S
... parents should also be tested for the abnormal gene. Examples of autosomal dominant disorders include Huntington's disease and neurofibromatosis-1 . See also: Autosomal recessive Heredity and disease Sex-linked dominant Sex-linked recessive
Autosomal dominant vitreoretinochoroidopathy (ADVIRC).
We report the second family recognised to have autosomal dominant vitreoretinochoroidopathy. The clinical features were (1) autosomal dominant inheritance; (2) peripheral, coarse pigmentary degeneration of the fundus for 360 degrees, with a relatively discrete posterior border in the equatorial region (this finding may be pathognomonic); (3) superficial punctate yellowish-white opacities in the retina; (4) various vascular abnormalities; (5) breakdown of the blood-retinal barrier; (6) retinal neovascularisation; (7) vitreous abnormalities; and (8) choroidal atrophy. Visual reduction was mainly due to macular oedema or vitreous haemorrhage. Images
Blair, N P; Goldberg, M F; Fishman, G A; Salzano, T
[Autosomal dominant polycystic kidney disease].
Autosomal dominant polycystic kiney disease is a hereditary systemic disorder, characterized by the developement of cysts, mainly in the kidney and liver, also with gastrointestinal and cardiovascular abnormalities. It affects 4 to 6 million people wordwide and accounts for end-stage renal disease in 7-10% of dialysis patients. The genetic penetrance is 100%, all affected individuals develop renal cysts until 70 years of age, and because of a great renal function reserve only about 50% of patients develop some degree of renal failure until the age of 60. Autosomal dominant polycystic kiney disease is a heterogeneous disorder, from a clinical as well as from a genetic point of view. There are at least three genes responsible for the disease: PKD-1 gene localized on chromosome 16p in the 16p13.3 segment which encodes Polycystin 1 protein similar to membrane receptor, PKD-2 gene localized on chromosome 4q in 4q13-23 segment which encodes Polycystin 2 protein wery similar to voltage L type Ca++ channel as well as Na+ channel and PKD-3 gene of unknown localization. Specific proteins participate in regulation od cell proliferation, apoptosis, secretion, polarity, cell-matrix interactions as cell-cell interactions and lead to the developement of cystic kidney disease. Renal manifestations of disease include structural (cyst development), functional (concentration alility falls), endocrine (renin erythropoietin) abnormalities and extra- renal manifestations. A routine diagnostic methods are good case-history about cystic kidney disease in family, ultrasonographic examination of kidneys and computerized tomography. In therapy of autosomal dominant polycystic kiney disease, low protein diets may help, treatment of arterial hypertension with ACE inhibitors and angiotensin II receptor blockers, the vasopressin V2 antagonists (VSR), rapamycin and long-acting somatostatin analogue may have some benefit. PMID:20804105
Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome.
Five members of a kindred with brachydactyly and distal symphalangism, normal stature, pes cavus, and scoliosis were ascertained. The pedigree was consistent with autosomal dominant inheritance. The combination of clinical and radiological features is believed to be distinct from those previously reported in patients with brachydactyly/symphalangism. PMID:671485
Sillence, D O
Arterial hypertension with brachydactyly in a 15-year-old boy
Autosomal dominant brachydactyly with hypertension is the only form of monogenic hypertension which is not sodium dependent. The disease is characterized by brachydactyly type E, short stature, arterial hypertension and aberrant loop of posterior inferior cerebellar artery (PICA) causing neurovascular conflict. So far the syndrome was described in one family in Turkey and two in Canada. We report a case
Mieczyslaw Litwin; Elzbieta Jurkiewicz; Katarzyna Nowak; Andrzej Kosciesza; Ryszard Grenda; Katarzyna Malczyk; Iwona Kosciesza
Deletion of 1 amino acid in Indian hedgehog leads to brachydactylyA1.
Brachydactyly type A1 is a limb malformation characterized by a uniform shortening of the middle phalanges in all digits. Mutations in the Indian hedgehog (IHH) gene were shown to be the cause of this autosomal dominant disorder. The IHH protein is known to be an important signaling molecule involved in chondrocyte formation. So far, only missense mutations in IHH have been reported to cause BrachydactylyA1. We report here on the first deletion in IHH, p.delE95, causing mild BrachydactylyA1 in a small Dutch family. This brings the total number of different mutations found to cause BDA1 to 7. PMID:18629882
Lodder, E M; Hoogeboom, A J M; Coert, J H; de Graaff, E
Genetics Home Reference: Autosomal dominant partial epilepsy with auditory features
... OMIM Genetic disorder catalog Conditions > Autosomal dominant partial epilepsy with auditory features (often shortened to ADPEAF ) On ... July 2008 What is ADPEAF? Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an uncommon form ...
Genetics Home Reference: Autosomal dominant nocturnal frontal lobe epilepsy
... disorder catalog Conditions > Autosomal dominant nocturnal frontal lobe epilepsy (often shortened to ADNFLE ) On this page: Description ... What is ADNFLE? Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon form of epilepsy that ...
Rhodopsin mutations in autosomal dominant retinitis pigmentosa.
DNA samples from 161 unrelated patients with autosomal dominant retinitis pigmentosa were screened for point mutations in the rhodopsin gene by using the polymerase chain reaction and denaturing gradient gel electrophoresis. Thirty-nine patients were found to carry 1 of 13 different point mutations at 12 amino acid positions. The presence or absence of the mutations correlated with the presence or absence of retinitis pigmentosa in 174 out of 179 individuals tested in 17 families. The mutations were absent from 118 control subjects with normal vision. Images
Sung, C H; Davenport, C M; Hennessey, J C; Maumenee, I H; Jacobson, S G; Heckenlively, J R; Nowakowski, R; Fishman, G; Gouras, P; Nathans, J
Extensive Mongolian Spots with Autosomal Dominant Inheritance
Background Mongolian spots are benign skin markings at birth which fade and disappear as the child grows. Often persistent extensive Mongolian spots are associated with inborn error of metabolism. We report thirteen people of the single family manifested with extensive Mongolian spots showing autosomal dominant inheritance. Case Presentation A one day old female child, product of second degree consanguineous marriage, born by normal vaginal delivery with history of meconium stained amniotic fluid and birth asphyxia. On examination the child showed extensive bluish discoloration of the body involving trunk and extremities in both anterior and posterior aspects associated with bluish discoloration of the tongue. A detailed family history revealed most of the family members manifested with extensive bluish discoloration of the body soon after birth which faded in the first few years of life and completely disappeared by puberty. Thus it was diagnosed to be extensive Mongolian spots with an autosomal dominant inheritance. Conclusion Knowledge about the natural history of extensive Mongolian spots, their inheritance and association with certain metabolic diseases mainly IEM and Mucopolysaccharidosis aids in the diagnosis and in order to improve the patient's prognosis.
Beeregowda, YC; Naveen, Kumar BV; Manjunatha, YC
Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases
Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the best known of a large family of inherited diseases characterized by the development of renal cysts of tubular epithelial cell origin. Autosomal dominant and recessive polycystic kidney diseases have overlapping but distinct pathogeneses. Identification of the causative mutated genes and elucidation of the function of their encoded
Peter C Harris; Vicente E Torres
Autosomal dominant sacral agenesis: Currarino syndrome
Autosomal dominant sacral agenesis is characterised by a partial agenesis of the sacrum typically involving sacral vertebrae S2-S5 only. Associated features include anorectal malformation, a presacral mass, and urogenital malformation. Together, these features have been defined as the Currarino syndrome. Recently, HLXB9 has been identified as the major causative gene in Currarino syndrome allowing identification of asymptomatic heterozygotes. In this review, we have performed an analysis of medical publications, and our own additional cases, to identify the range of malformations and complications that occur. We have also estimated risks of malformation in heterozygotes by using Weinburg's proband method on families personally known to us in order to provide accurate genetic counselling information.???Keywords: sacral agenesis; presacral mass; anorectal malformation; Currarino triad
Lynch, S. A.; Wang, Y.; Strachan, T; Burn, J.; Lindsay, S.
Epigenetics and autosomal dominant polycystic kidney disease?
The roles of epigenetic modulation of gene expression and protein functions in autosomal dominant polycystic kidney disease (ADPKD) have recently become the focus of scientific investigation. Evidence generated to date indicates that one of the epigenetic modifiers, histone deacetylases (HDACs), are important regulators of ADPKD. HDACs are involved in regulating the expression of the Pkd1 gene and are the target of fluid flow-induced calcium signal in kidney epithelial cells. Pharmacological inhibition of HDAC activity has been found to reduce the progression of cyst formation and slow the decline of kidney function in Pkd1 conditional knockout mice and Pkd2 knockout mice, respectively, implicating the potential clinical application of HDAC inhibitors on ADPKD. Since the expression of HDAC6 is upregulated in cystic epithelial cells, the potential roles of HDAC6 in regulating cilia resorption and epidermal growth factor receptor (EGFR) trafficking through deacetylating ?-tubulin and regulating Wnt signaling through deacetylating ?-catenin are also discussed. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
Li, Xiaogang
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy is an autosomal dominant disease affecting small vessels and often resulting in subcortical infarcts. A skin biopsy may facilitate its diagnosis as the cutaneous surface is much easier to sample than the central nervous system's tissue. Unfortunately, there is no effective treatment available today.
McLeod, Michael; Torchia, Daniele; Romanelli, Paolo
Clinical profile of autosomal dominant polycystic liver disease
Most reports on the natural history, manifestations, and treatment of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The purpose of this study was to develop a clinical profile of isolated autosomal dominant polycystic liver disease (ADPLD) using nonaffected family members as controls. The study included 146 probands,
Qi Qian; Airong Li; Bernard F. King; Patrick S. Kamath; Donna J. Lager; John Huston; Clarence Shub; Sonia Davila; Stefan Somlo; Vicente E. Torres
Weill-Marchesani syndrome--possible linkage of the autosomal dominant form to 15q21.1.
Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait (McKusick 277600). We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals. PMID:8914744
Wirtz, M K; Samples, J R; Kramer, P L; Rust, K; Yount, J; Acott, T S; Koler, R D; Cisler, J; Jahed, A; Gorlin, R J; Godfrey, M
A new mutation in the gene ROR2 causes brachydactyly type B1.
Brachydactyly type B, an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails, can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is caused by mutations in the receptor tyrosine kinase gene ROR2, which maps to chromosome 9q22, whereas BDB2 is caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Here, we report a three-generation Chinese family with dominant inheritance of the BDB1 limb phenotype. Sequence analysis identified a novel heterozygous base deletion (c.1396-1398delAA) in the gene ROR2 in all affected family members. This new deletion is expected to produce a truncated Ror2 protein with a new polypeptide of 57 amino acids at the C-terminal. PMID:24954533
Huang, Dan; Jiang, Shujuan; Zhang, Yuanyuan; Liu, Xiaoliang; Zhang, Jiubin; He, Rong
An Unusual Cardiac Manifestation in Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease is a common hereditary disorder characterized by renal and extrarenal, cystic and noncystic manifestations. Connective tissue defects, including cerebral aneurysm, meningeal diverticula, abdominal wall hernias, intestinal diverticula, and cardiac valvular abnormalities, are widely known manifestations. Instead intracardiac aneurysms have never been reported in adults with autosomal dominant polycystic kidney disease. We describe a 65-year-old patient with end-stage renal disease due to autosomal dominant polycystic kidney disease and an atrial septum aneurysm associated with platypnoea-orthodeoxia syndrome.
Catapano, Fausta; Pancaldi, Stefano; Napoleone, Carlo Pace; De Sanctis, Lucia Barbara; Gargiulo, Gaetano; Emiliani, Giuseppe; Santoro, Antonio
Autosomal dominant hypoparathyroidism: a proband with concurrent nephrogenic diabetes insipidus.
In this paper we report an extended family with well documented autosomal dominant hypoparathyroidism which was ascertained through a proband with coincident nephrogenic diabetes insipidus. Clinical findings were limited to a slight decrease in overall stature and to clinical signs of hypocalcaemia. Intelligence was normal and two patients were asymptomatic. Published reports have established that autosomal dominant, autosomal recessive, and sex linked recessive familial isolated hypoparathyroidism exist. However, in almost half the reported families an X linked dominant aetiology cannot be excluded and, at present, clinical criteria provide only minimal aid in distinguishing between the different genetic types. There remains a need for detailed documentation of further families were the pattern of inheritance is clear.
Hunter, A G; Heick, H; Poznanski, W J; McLaine, P N
Evidence for further genetic heterogeneity in autosomal dominant retinitis pigmentosa
We have investigated the possible involvement of further genetic heterogeneity in autosomal dominant retinitis pigmentosa using a previously unreported large Irish family with the disease. We have utilized polymorphic microsatellite markers to exclude the disease gene segregating in this family from 3q, 6p, and the pericentric region of 8, that is, each of the three chromosomal regions to which adRP loci are known to map. Hence, we provide definitive evidence for the involvement of a fourth locus in autosomal dominant retinitis pigmentosa. 25 refs., 2 figs.
Kumar-Singh, R.; Kenna, P.F.; Farrar, G.J.; Humphries, P. (Trinity College, Dublin (Ireland))
Autosomal dominant polycystic kidney disease: the last 3 years
Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the
Vicente E Torres; Peter C Harris
A "reverse genetic" approach to autosomal dominant polycystic kidney disease
Biochemical, anatomical, pathophysiological and clinical studies of autosomal dominant "adult-type" polycystic kidney disease have cast little light on the underlying biochemical defect which causes the disease. The advent of recombinant DNA technology permits a novel approach to its pathophysiology. In this approach, termed "reverse genetics", the mutation which produces the disease is first localised by genetic linkage. This is followed
Stephen T. Reeders
Gene therapy in animal models of autosomal dominant retinitis pigmentosa
Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success.
Rossmiller, Brian; Mao, Haoyu
[Polycystic liver disease without autosomal dominant polycystic kidney disease].
Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively. PMID:14658173
Peces, R; González, P; Venegas, J L
Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for ?40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA
Nůria Fonknechten; Delphine Mavel; Claire-Sophie Davoine; Corinne Cruaud; Dominikus Boentsch; Delphine Samson; Paula Coutinho; Michael Hutchinson; Paul McMonagle; Jean-Marc Burgunder; Antonio Tartaglione; Olivier Heinzlef; Nollaig Parfrey; Alexis Brice; Bertrand Fontaine; Jean Weissenbach; Alexandra Dürr; Jamilé Hazan
Molecular basis of autosomal-dominant polycystic kidney disease
. Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery\\u000a that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1\\u000a and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells
A. R. Gallagher; S. Hidaka; N. Gretz; R. Witzgall
Autosomal dominant polycystic kidney disease: the last 3 years
Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective therapies. The purpose of this review is to update the core of knowledge in this area with recent publications that have appeared during 2006–2009.
Torres, Vicente E.; Harris, Peter C.
Lymphocyte infiltration in CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy
Purpose To describe immunohistopathological findings in autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). Methods An enucleated eye specimen from a patient with Stage V ADNIV was examined using standard histopathological methods and lymphocyte markers. Results A c.731T>C CAPN5 mutation resulted in a p.Leu244Pro substitution in calpain-5. The eye showed exudative retinal detachment and neovascularization, intraocular fibrosis, and features of phthisis bulbi. Chronic inflammatory CD3-positive cell infiltrates were identified throughout the uvea, vitreous and retina, consistent with chronic uveitis. Conclusion Mutations in CAPN5 trigger autoimmune uveitis characterized by inflammatory T-cells and severe neovascularization.
Mahajan, Vinit B; Lin, Jonathan H
Multiple cysts in the liver autosomal dominant polycystic liver disease.
A 45-year-old woman was admitted because of abdominal pain and a feeling of fullness. Ultrasound and CT scan of the abdomen showed a massively enlarged liver with hundreds of cysts and displacement of the right kidney. There were no cysts in the kidneys. Because several members of her family also had multiple cysts in the liver, the diagnosis of autosomal dominant polycystic liver disease (PCLD) was made. Genetic analysis demonstrated a protein kinase C substrate 80 K-H (PR KCSH) gene mutation (1338-2A>G) and confirmed the clinical diagnosis. A brief review of the genetics and possible treatments is given. PMID:16788219
Karimbeg, A A; Loffeld, R J L F
Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease
Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.
Benzinger, Tammie L. S.; Blazey, Tyler; Jack, Clifford R.; Koeppe, Robert A.; Su, Yi; Xiong, Chengjie; Raichle, Marcus E.; Snyder, Abraham Z.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Fagan, Anne M.; Goate, Alison; Marcus, Daniel S.; Aisen, Paul S.; Christensen, Jon J.; Ercole, Lindsay; Hornbeck, Russ C.; Farrar, Angela M.; Aldea, Patricia; Jasielec, Mateusz S.; Owen, Christopher J.; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A.; Ringman, John; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen; Correia, Stephen; Schofield, Peter R.; Masters, Colin L.; Rowe, Christopher; Villemagne, Victor L.; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N.; Fox, Nick C.; Cash, David M.; Weiner, Michael W.; Holtzman, David M.; Buckles, Virginia D.; Moulder, Krista; Morris, John C.
Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis
Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.
Martignetti, John A.; Tian, Lifeng; Li, Dong; Ramirez, Maria Celeste M.; Camacho-Vanegas, Olga; Camacho, Sandra Catalina; Guo, Yiran; Zand, Dina J.; Bernstein, Audrey M.; Masur, Sandra K.; Kim, Cecilia E.; Otieno, Frederick G.; Hou, Cuiping; Abdel-Magid, Nada; Tweddale, Ben; Metry, Denise; Fournet, Jean-Christophe; Papp, Eniko; McPherson, Elizabeth W.; Zabel, Carrie; Vaksmann, Guy; Morisot, Cyril; Keating, Brendan; Sleiman, Patrick M.; Cleveland, Jeffrey A.; Everman, David B.; Zackai, Elaine; Hakonarson, Hakon
Autosomal dominant epidermodysplasia verruciformis: a clinicotherapeutic experience in two cases.
Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by a unique susceptibility to cutaneous infection by a group of phylogenetically related human papilloma viruses (HPVs). These patients show a defect in cell-mediated immunity specific toward the causative HPVs that lead to lifelong disease. The defect is usually inherited as autosomal recessive trait and presents clinically with plane warts, pityriasis versicolor-like lesions and reddish verrucous plaques. Dysplastic and malignant changes in the form of actinic keratoses, Bowen's disease and squamous cell carcinoma (SCC) are common but metastasis occurs rarely. A totally effective treatment against EV is as yet highly desirable. Two siblings having autosomal dominant EV presented with multiple actinic keratoses in addition to classic lesions. One of them had also developed well-differentiated SCC over forehead with metastases to regional lymph nodes. They were treated with combination of excision of small malignant/premalignant lesions, topical 5-flurouracil and sun protection. Additionally, elective excision/grafting of large SCC was performed after chemotherapy/radiotherapy in patient with metastatic SCC. Oral acitretin (25 mg/day) was of benefit in the other patient. Overall clinicotherapeutic experience in both the patients is discussed here. PMID:20826999
Vohra, Surbhi; Sharma, Nand Lal; Shanker, Vinay; Mahajan, Vikram K; Jindal, Nidhi
Parkinsonism associated with autosomal dominant bilateral striopallidodentate calcinosis.
Bilateral striopallidodentate calcinosis (BSPDC, also known as Fahr's disease, a misnomer), is a rare disorder where bilateral, almost symmetric, calcium and other mineral deposits occur in subcortical nuclei and white matter. Neurological manifestations vary but movement disorders are the most common. Of the movement disorders, parkinsonism predominates. We describe 6 patients with BSPDC associated with parkinsonism. Of the 6 patients, one patient from an autosomal dominantly inherited family who responded to levodopa, showed Lewy bodies in substantia nigra neurons and changes consistent with BSPDC. Another patient, from the same family with clinical evidence of parkinsonism and radiological and neuropathological evidence of BSPDC, did not show Lewy bodies. Ten patients with BSPDC and parkinsonism (without evidence of parathyroid dysfunction) were found in the literature. When parkinsonism is associated with dementia and cerebellar signs, obtaining a CT scan may be helpful as BSPDC often presents with the above three conditions. PMID:11344012
Manyam, B V.; Walters, A S.; Keller, I A.; Ghobrial, M
Weaver syndrome: autosomal dominant inheritance of the disorder.
Weaver syndrome (WS), a condition first described in 1974 by Weaver et al., consists of macrosomia, advanced skeletal age, characteristic pattern of facial and radiographic anomalies, and contractures. Although there have been three reports of close relatives (sibs or both parent and offspring) affected with this condition, the syndrome generally occurs sporadically, and the recurrence risk in sporadic cases appears to be low. We report here on a family in which the propositus and his sister were born with the facial phenotype, club feet, and macrosomia characteristic of WS. Their father had macrosomia and macrocephaly as an adult, and childhood photos show clearly that he has WS. Two sisters of the propositus have had normal growth and development. The syndrome in this family appears to be inherited in an autosomal dominant fashion. PMID:9781912
Proud, V K; Braddock, S R; Cook, L; Weaver, D D
Autosomal dominant inheritance of left ventricular outflow tract obstruction.
Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction (LVOTO), consisting of hypoplastic left heart (HLHS) or left ventricle (HLV), aortic valve stenosis (AS) and bicuspid aortic valve (BAV), hypoplastic aortic arch (HAA), and coarctation of the aorta (CoA). LVOTO in these families shows a wide clinical spectrum with some family members having severe anomalies such as hypoplastic left heart, and others only minor anomalies such as mild aortic valve stenosis. This supports the suggestion that all anomalies of the LVOTO spectrum are developmentally related and can be caused by a single gene defect. PMID:15712195
Wessels, Marja W; Berger, Rolf M F; Frohn-Mulder, Ingrid M E; Roos-Hesselink, Jolien W; Hoogeboom, Jeanette J M; Mancini, Grazia S; Bartelings, Margot M; Krijger, Ronald de; Wladimiroff, Jury W; Niermeijer, Martinus F; Grossfeld, Paul; Willems, Patrick J
Genetics Home Reference: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
... attack, such as high blood pressure and high cholesterol, although some affected individuals might also have these ... understanding CADASIL? apoptosis ; arteriopathy ; autosomal ; autosomal dominant ; cell ; cholesterol ; dementia ; epilepsy ; familial ; gene ; heart attack ; imaging ; infarct ; ...
Ribozyme gene therapy for autosomal dominant retinal disease.
Gene delivery to cells of the retina, particularly to photoreceptor cells, has broad potential both for answering basic questions of retinal biology and for more applied therapeutic purposes. The use of ribozymes as therapy for autosomal dominant retinal diseases is a promising technique, and the theoretical and practical basis for their use is discussed. The process involves designing and testing ribozymes first in vitro and then in animal models of retinal disease. Viral vectors based on the nonpathogenic human adeno-associated virus, when coupled with the strong, rod photoreceptor specific opsin promoter, offer an efficient and nontoxic way to deliver and express ribozymes in photoreceptor cells for long time periods of time. Effective ribozyme-mediated therapy also demands careful in vitro analysis of a ribozyme's ability to efficiently and specifically distinguish between mutant and wild type RNAs. Finally, effective demonstration of therapy in an animal model requires careful analysis of any rescue effect in the retina using multiple criteria, including biochemical, structural and physiological assays. For this purpose, ribozyme therapy in a transgenic rat model of retinitis pigmentosa containing a dominant rod opsin mutation (proline-to-histidine change at position 23) is discussed in detail. PMID:10834402
Hauswirth, W W; LaVail, M M; Flannery, J G; Lewin, A S
Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy
Autosomal-dominant congenital stromal corneal dystrophy (CSCD) is a human genetic disease characterized by corneal opacities beginning shortly after birth. It is linked to a frameshift mutation in decorin, resulting in a C-terminal truncation lacking 33 amino acids that includes the "ear" repeat, a feature specific for small leucine-rich proteoglycans. Our goals are to elucidate the roles of the mutant decorin in CSCD pathophysiology and to decipher the mechanism whereby mutant decorin affects matrix assembly. A novel animal model that recapitulates human CSCD was generated. This transgenic mouse model targets expression of truncated decorin to keratocytes, thereby mimicking the human frameshift mutation. Mutant mice expressed both wild-type and mutant decorin. Corneal opacities were found throughout, with increased severity toward the posterior stroma. The architecture of the lamellae was disrupted with relatively normal lamellae separated by regions of abnormal fibril organization. Within abnormal zones, the interfibrillar spacing and the fibril diameters were increased. Truncated decorin negatively affected the expression of endogenous decorin, biglycan, lumican, and keratocan and positively affected fibromodulin. Our results provide a mechanistic explanation for the generation of corneal opacities in CSCD. Thus, truncated decorin acts in a dominant-negative manner to interfere dually with matrix assembly and binding to receptor tyrosine kinases, thereby causing abnormal expression of endogenous small leucine-rich proteoglycans leading to structural abnormalities within the cornea and vision loss.
Chen, Shoujun; Sun, Mei; Meng, Xianmin; Iozzo, Renato V.; Kao, Winston W.-Y.; Birk, David E.
Autosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results renal failure. The understanding the pathogenesis of ADPKD has advanced significantly since the discovery of the two causative genes, PKD1 or PKD2. Dominantly inherited gene mutations followed by somatic second hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a non-motile microtubule based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell signaling pathways that have been implicated in the pathways related to PKD1 and PKD2.
Gallagher, Anna Rachel; Germino, Gregory G.; Somlo, Stefan
Familial central precocious puberty suggests autosomal dominant inheritance.
The prevalence of precocious puberty is higher in certain ethnic groups, and some cases may be familial. The aim of this study was to investigate the mode of inheritance of familial precocious puberty and to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to our center for suspected precocious puberty between January 1, 1997, and December 31, 2000, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy) (27.5%). Data of the familial and sporadic cases were compared. The familial group was characterized by a significantly lower maternal age at menarche than the sporadic group (mean, 11.47 +/- 1.96 vs. 12.66 +/- 1.18 yr; P = 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; P = 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0.38 (0.45 after exclusion of young siblings) assuming incomplete penetrance and 0.58 (0.65 after exclusion of young siblings) assuming complete ascertainment. These results suggest autosomal dominant transmission with incomplete, sex-dependent penetrance. PMID:15070947
de Vries, Liat; Kauschansky, Arieh; Shohat, Mordechai; Phillip, Moshe
Autosomal dominant familial erythrocytosis due to autonomous erythropoietin production
A family is described in which four members spanning three consecutive generations have erythrocytosis associated with a normal hemoglobin oxygen affinity. When bone marrow from one affected family member was cultured in vitro, erythroid colonies formed only when erythropoietin was added to the culture. Serum erythropoietin, measured by radioimmunoassay, was significantly elevated above normal in each of the affected family members. Bioassayable erythropoietin was detected in the urine of two of the three affected family members. In two of the affected family members, erythropoietin was measured in serum by radioimmunoassay and in urine by bioassay before and for 4 days following an isovolemic phlebotomy, which reduced the red cell mass by 20%. Neither serum nor urinary erythropoietin levels changed following phlebotomy. The erythrocytosis in this family appears to be secondary to inappropriately increased erythropoietin production unassociated with a decrease in the blood oxygen-carrying capacity. This is the first instance in which autonomous erythropoietin production appears to be inherited on an autosomal dominant basis.
Distelhorst, C.W. (Ohio State Univ. College of Medicine, Columbus); Wagner, D.S.; Goldwasser, E.; Adamson, J.W.
Two families with autosomal dominant progressive external ophthalmoplegia
Objectives: We report here the clinical and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia (adPEO). Patients and methods: The examination of index patients included a detailed clinical characterisation, histological analysis of muscle biopsy specimens, and genetic testing of mitochondrial and nuclear DNA extracted from muscle and leucocytes. Results: Index patients in both families presented with PEO and developed other clinical disease manifestations, such as myopathy and cardiomyopathy (patient 1) and axonal neuropathy, diabetes mellitus, hearing loss, and myopathy (patient 2), later in the course of illness. Both patients had ragged red fibres on muscle histology. Southern blot of mtDNA from muscle of patient 2 showed multiple deletions. In this case, a novel heterozygous missense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle. The mutation co-segregated with the clinical phenotype in the family and was not detected in 150 control chromosomes. In the other index patient, sequencing of ANT1, C10orf2 (encoding for Twinkle), and POLG1 did not reveal pathogenic mutations. Conclusions: Our cases illustrate the clinical variability of adPEO, add a novel pathogenic mutation in Twinkle (F485L) to the growing list of genetic abnormalities in adPEO, and reinforce the relevance of other yet unidentified genes in mtDNA maintenance and pathogenesis of adPEO.
Kiechl, S; Horvath, R; Luoma, P; Kiechl-Kohlendorf..., U; Wallacher-Scholz, B; Stucka, R; Thaler, C; Wanschitz, J; Suomalainen, A; Jaksch, M; Willeit, J
Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-? (TGF?) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGF? and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL.
Hu, Qirui; Shifren, Adrian; Sens, Carla; Choi, Jiwon; Szabo, Zoltan; Starcher, Barry C.; Knutsen, Russell H.; Shipley, J. Michael; Davis, Elaine C.; Mecham, Robert P.; Urban, Zsolt
Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease
Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal-dominant polycystic kidney disease (ADPKD). Hypertension is a common early symptom of ADPKD, and occurs in approximately 60% of patients before renal function has become impaired. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable in ADPKD. Left ventricular hypertrophy, which is a powerful, independent risk factor for cardiovascular morbidity and mortality, also occurs frequently in patients with ADPKD. Both hypertension and left ventricular hypertrophy have important roles in cardiovascular complications in these individuals. Moreover, biventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and impaired coronary flow velocity reserve are present even in young patients with ADPKD who have normal blood pressure and well-preserved renal function. These findings suggest that cardiovascular involvement starts very early in the course of ADPKD. Intracranial and extracranial aneurysms and cardiac valvular defects are other potential cardiovascular problems in patients with ADPKD. Early diagnosis and treatment of hypertension, with drugs that block the renin-angiotensin-aldosterone system, has the potential to decrease the cardiovascular complications and slow the progression of renal disease in ADPKD.
Ecder, Tevfik; Schrier, Robert W.
Autosomal dominant arteriopathic leuko-encephalopathy and Alzheimer's disease.
A 49-year-old man suffered from progressive dementia and seizures leading to death after 2 years. CT scans showed severe cortical-subcortical atrophy and hypodensity of the white matter. His father had died at about the same age with similar clinical signs. Two sisters and one brother were also affected. Neuropathological study revealed predominant involvement of the cerebral white matter with myelin loss, gliosis and type I lacunes. The small arteries and arterioles of the white matter and basal ganglia, and, to a lesser extent those of the subarachnoidal space, displayed fibrosis and replacement of the media by an eosinophilic, PAS positive, Congo Red negative, granular substance. Electron microscopy showed swollen myocytes surrounded by collagen, elastin and a compact electron-dense material. Immunofluorescence using antibodies against IgA, IgG, IgM, C1q and C3 stained the abnormal media weakly. In the cortex, there were diffuse senile plaques and neurofibrillary tangles. Immunohistochemistry demonstrated beta/A4 positive material in cortical senile plaques but not in arterial walls. Adventitial macrophages were, however, immunoreactive for gamma-trace. Systemic arterioles were normal. The vascular changes and leukoencephalopathy are comparable to those described in 'Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy' (CADASIL). Similar vascular changes were also observed in nonfamilial cases. An association with Alzheimer changes in the cortex has not been described previously. The relationship between both diseases and the role of each in the causation of the dementia is unclear. PMID:8208337
Gray, F; Robert, F; Labrecque, R; Chrétien, F; Baudrimont, M; Fallet-Bianco, C; Mikol, J; Vinters, H V
T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy
Purpose Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a familial blinding disease of unknown pathophysiology. The eyes and sera from patients with ADNIV were studied to understand the immune response in this condition. Methods The clinical case of an ADNIV patient was reviewed. Eye specimens from two donors with ADNIV were examined with a panel of standard histopathological stains and immunohistochemical markers. These findings were compared to specimens of noninflammatory eye disease. Sera from twelve patients were also tested against retinal protein western blots for the presence of autoretinal antibodies. Results Each of the ADNIV and control eyes showed degenerative features of phthisis bulbi. Immunohistological stains revealed a supraciliary T-cell infiltrate in ADNIV eyes composed of cluster of differentiation-4 (CD4) positive and cluster of differentiation-8 (CD8)-positive cells. No immunoglobulin or B cells were detected in these eyes. Inflammatory cells were absent from the control eyes. No specific autoretinal antibodies were detected in ADNIV sera. Conclusions Aberrant T-cell-mediated processes may underlie ADNIV, and therapeutics directed at T cells may better manage inflammation in these patients. Genes related to T-cell function are high priority screening candidates.
Mahajan, Vinit B.; Vallone, John G.; Lin, Jonathan H.; Mullins, Robert F.; Ko, Audrey C.; Folk, James C.
New treatments for autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and results from mutations in PKD1 or PKD2. Cyst initiation and expansion arise from a combination of abnormal cell proliferation, fluid secretion and extracellular matrix defects and results in kidney enlargement and interstitial fibrosis. Since its first description over 200 years ago, ADPKD has been considered an untreatable condition and its management is limited to blood pressure reduction and symptomatic treatment of disease complications. Results of the recently reported TEMPO 3/4 trial thus represent a paradigm shift in demonstrating for the first time that cystic disease and loss of renal function can be slowed in humans. In this paper, we review the major therapeutic strategies currently being explored in ADPKD including a range of novel approaches in preclinical models. It is anticipated that the clinical management of ADPKD will undergo a revolution in the next decade with the translation of new treatments into routine clinical use. PMID:23594398
Chang, Ming-Yang; Ong, Albert C M
Renal transplantation in autosomal dominant polycystic kidney disease.
In patients with autosomal dominant polycystic kidney disease (ADPKD) evaluated for kidney transplantation, issues related to native nephrectomy, cystic liver involvement, screening for intracranial aneurysms and living-related kidney donation deserve special consideration. Prophylactic native nephrectomy is restricted to patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. Patients with liver involvement require pretransplant imaging. Selection of patients for pretransplant screening of intracranial aneurysms should follow the general recommendations for patients with ADPKD. In living related-donor candidates aged <30 years and at-risk of ADPKD, molecular genetic testing should be carried out when ultrasonography and MRI findings are normal or equivocal. After kidney transplantation, patient and graft survival rates are excellent and the volume of native kidneys decreases. However, liver cysts continue to grow and treatment with a somatostatin analogue should be considered in patients with massive cyst involvement. Cerebrovascular events have a marginal effect on post-transplant morbidity and mortality. An increased risk of new-onset diabetes mellitus and nonmelanoma skin cancers has been reported, but several studies have challenged these findings. Finally, no data currently support the preferential use of mammalian target of rapamycin inhibitors as immunosuppressive agents in transplant recipients with ADPKD. PMID:24935705
Kanaan, Nada; Devuyst, Olivier; Pirson, Yves
Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history
Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.
Palmer, S.E.; Stephens, K.; Dale, D.C. [Univ. of Washington, Seattle, WA (United States)
Molecular cytogenetic aberrations in autosomal dominant polycystic kidney disease tissue.
Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-alpha/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35-36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression. PMID:12538736
Gogusev, Jean; Murakami, Ichiro; Doussau, Mireille; Telvi, Louise; Stojkoski, Alexandre; Lesavre, Philippe; Droz, Dominique
Molecular diagnostics for autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a common nephropathy caused by mutations in either PKD1 or PKD2. Mutations in PKD1 account for ~85% of cases and cause more severe disease than mutations in PKD2. Diagnosis of ADPKD before the onset of symptoms is usually performed using renal imaging by either ultrasonography, CT or MRI. In general, these modalities are reliable for the diagnosis of ADPKD in older individuals. However, molecular testing can be valuable when a definite diagnosis is required in young individuals, in individuals with a negative family history of ADPKD, and to facilitate preimplantation genetic diagnosis. Although linkage-based diagnostic approaches are feasible in large families, direct mutation screening is generally more applicable. As ADPKD displays a high level of allelic heterogeneity, complete screening of both genes is required. Consequently, such screening approaches are expensive. Screening of individuals with ADPKD detects mutations in up to 91% of cases. However, only ~65% of patients have definite mutations with ~26% having nondefinite changes that require further evaluation. Collation of known variants in the ADPKD mutation database and systematic scoring of nondefinite variants is increasing the diagnostic value of molecular screening. Genic information can be of prognostic value and recent investigation of hypomorphic PKD1 alleles suggests that allelic information may also be valuable in some atypical cases. In the future, when effective therapies are developed for ADPKD, molecular testing may become increasingly widespread. Rapid developments in DNA sequencing may also revolutionize testing.
Harris, Peter C.; Rossetti, Sandro
Psychonephrology: psychological aspects in autosomal dominant polycystic kidney disease.
The biological, physical and psychological burden of a chronic disease has an impact on the quality of life of people who suffer from it. The perception of quality of life is affected by psychological disorders such as anxiety and depression that have a high prevalence in people with chronic kidney disease (CKD). These factors are also linked to lower life expectancy. It is therefore surprising that the psychological aspects of people with autosomal dominant polycystic kidney disease (ADPKD) have received so little attention in the medical literature, despite their importance for the overall health of these patients. The relatively new discipline called psychonephrology provides a broader view of the impact that these aspects have on individuals with chronic kidney disease, with a consequent practical application. In this article, we examine the consequences and prevalence of psychological problems that can be related to CKD and ADPKD. Firstly, we will focus on the field of CKD and ADPKD within the scope of psychonephrology. Secondly, the article introduces the concept of quality of life as a basic pillar of health that is affected when a person is diagnosed with CKD. Thirdly, we will present a summary of the main research related to anxiety and depression disorders in CKD and ADPKD. The article will conclude by synthesising findings from the different lines of research undertaken. PMID:22130288
Pérez Domínguez, T S; Rodríguez Pérez, A; Buset Ríos, N; Rodríguez Esparragón, F; García Bello, M A; Pérez Borges, P; Parodis López, Y; Rodríguez Pérez, J C
Detection of novel genetic variation in autosomal dominant retinitis pigmentosa.
We explored an approach to detect disease-causing sequence variants in 448 candidate genes from five index cases of autosomal dominant retinitis pigmentosa (adRP) by sequence DNA capture and next-generation DNA sequencing (NGS). Detection of sequence variants was carried out by sequence capture NimbleGen and NGS in a SOLiD platform. After filtering out variants previously reported in genomic databases, novel potential adRP-causing variants were validated by dideoxy capillary electrophoresis (Sanger) sequencing and co-segregation in the families. A total of 55 novel sequence variants in the coding or splicing regions of adRP candidate genes were detected, 49 of which were confirmed by Sanger sequencing. Segregation of these variants in the corresponding adRP families showed three variants present in all the RP-affected members of the family. A novel mutation, p.L270R in IMPDH1, was found to be disease causing in one family. In another family a variant, p.M96T in the NRL gene was detected; this variant was previously reported as probably causing adRP. However, the previously reported p.A76V mutation in NRL as a cause of RP was excluded by co-segregation in the family. We discuss the benefits and limitations of our approach in the context of mutation detection in adRP patients. PMID:23534816
Borrŕs, E; de Sousa Dias, M; Hernan, I; Pascual, B; Mańé, B; Gamundi, M J; Delás, B; Carballo, M
Urine proteome of autosomal dominant polycystic kidney disease patients
Background Autosomal dominant polycystic kidney disease (ADPKD) is responsible for 10% of cases of the end stage renal disease. Early diagnosis, especially of potential fast progressors would be of benefit for efficient planning of therapy. Urine excreted proteome has become a promising field of the search for marker patterns of renal diseases including ADPKD. Up to now however, only the low molecular weight fraction of ADPKD proteomic fingerprint was studied. The aim of our study was to characterize the higher molecular weight fraction of urinary proteome of ADPKD population in comparison to healthy controls as a part of a general effort aiming at exhaustive characterization of human urine proteome in health and disease, preceding establishment of clinically useful disease marker panel. Results We have analyzed the protein composition of urine retentate (>10?kDa cutoff) from 30 ADPKD patients and an appropriate healthy control group by means of a gel-free relative quantitation of a set of more than 1400 proteins. We have identified an ADPKD-characteristic footprint of 155 proteins significantly up- or downrepresented in the urine of ADPKD patients. We have found changes in proteins of complement system, apolipoproteins, serpins, several growth factors in addition to known collagens and extracellular matrix components. For a subset of these proteins we have confirmed the results using an alternative analytical technique. Conclusions Obtained results provide basis for further characterization of pathomechanism underlying the observed differences and establishing the proteomic prognostic marker panel.
Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease.
Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations, such as depression, anxiety, obsessive-compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is considered normal in Segawa disease. Our aim was to investigate neuropsychiatric symptoms and intelligence quotients (IQ) in a series of individuals with adGTPCH deficiency. The assessment included a structured clinical interview following the DSM-IV-TR's guidelines, Beck's Depression Inventory, the State-Trait Anxiety Inventory, the Maudsley Obsessive-Compulsive Questionnaire, the Barratt Impulsiveness Scale-11 (BIS-11), the Oviedo Sleep Questionnaire, the Pittsburgh Sleep Quality Index, and the Wechsler Adult Intelligence Scale-Third Edition. Equivalent tests were applied to pediatric patients as appropriate for their age group. Fourteen patients with adGTPCH deficiency were evaluated (seven adult and seven pediatric patients). Depression, anxiety, and obsessive-compulsive symptoms were not more common than expected in the general population. However, the seven adults showed impulsivity in the BIS-11; nine individuals had an IQ in the range of borderline intellectual functioning to mild mental retardation, and sleep disturbances were found in four individuals. We found no differences between these results and the motor impairment. In conclusion, our findings would suggest that cognitive impairment, and impulsivity in adults, may be associated with Segawa disease. PMID:21556877
López-Laso, Eduardo; Sánchez-Raya, Araceli; Moriana, Juan Antonio; Martínez-Gual, Eduardo; Camino-León, Rafael; Mateos-González, María Elena; Pérez-Navero, Juan Luis; Ochoa-Sepúlveda, Juan José; Ormazabal, Aida; Opladen, Thomas; Klein, Christine; Lao-Villadóniga, José Ignacio; Beyer, Katrin; Artuch, Rafael
Diagnosis and Screening of Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and accounts for ?5% of end-stage renal disease (ESRD) population in the United States. The disorder is characterized by the focal and sporadic development of renal cysts, which increase in size and number with age. Mutations of PKD1 and PKD2 account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of ESRD. In general, renal ultrasonography is commonly used for the diagnosis of ADPKD and age-dependent criteria have been defined for subjects at-risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinic setting is unclear since their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage or gene-based direct sequencing are now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living-related kidney donors. Here, we review the clinical utilities and limitations of both imaging- and molecular-based diagnostic tests, and outline our approach for the evaluation of individuals suspected to have ADPKD.
Pei, York; Watnick, Terry
Impaired default network functional connectivity in autosomal dominant Alzheimer disease
Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L.S.; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew J.; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.
Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis
Cyclic hematopoiesis (CH, or cyclic neutropenia) is a rare disease manifested by transient severe neutropenia that recurs approximately every 21 days. The hematologic profile of families with the autosomal dominant form (ADCH) has not been well characterized, and it is unknown if the phenotype is distinct from the more common sporadic congenital or acquired forms of CH. We studied nine ADCH families whose children displayed typical CH blood patterns. Pedigrees confirmed dominant inheritance without evidence of heterogeneity or decreased penetrance; three pedigrees suggested new mutations. Families were Caucasian with exception of one with a Cherokee Native American founder. A wide spectrum of symptom severity, ranging from asymptomatic to life-threatening illness, was observed within families. The phenotype changed with age. Children displayed typical neutrophil cycles with symptoms of mucosal ulceration, lymphadenopathy, and infections. Adults often had fewer and milder symptoms, sometimes accompanied by mild chronic neutropenia without distinct cycles. While CH is commonly described as {open_quotes}benign{close_quotes}, four children in three of the nine families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases. Genetic counseling requires specific histories and complete blood counts in relatives at risk to assess status regardless of symptoms, especially to determine individuals with new mutations. We propose diagnostic criteria for ADCH in affected children and adults. Recombinant human granulocyte colony-stimulating factor treatment resulted in dramatic improvement of neutropenia and morbidity. The differential diagnosis from other forms of familial neutropenia is reviewed. 45 refs., 4 figs., 1 tab.
Palmer, S.E. [Univ. of Washington, Seattle, WA (United States)] [Univ. of Washington, Seattle, WA (United States); [Univ. of Texas Health Science Center, San Antonio, TX (United States); Dale, D.C. [Univ. of Washington, Seattle, WA (United States)] [Univ. of Washington, Seattle, WA (United States)
Connexin46 mutations in autosomal dominant congenital cataract.
Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.
Mackay, D; Ionides, A; Kibar, Z; Rouleau, G; Berry, V; Moore, A; Shiels, A; Bhattacharya, S
Autosomal dominant osteopetrosis revisited: lessons from recent studies.
Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis. PMID:23744590
Bollerslev, Jens; Henriksen, Kim; Nielsen, Morten Frost; Brixen, Kim; Van Hul, Wim
[CADASIS. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalophathy].
CADASIL is an inherited arterial disease of the brain with an autosomal dominant pattern of transmission. The mapping of the affected gene in 1993 allowed us to describe the natural history of the disease. In some patients, the disease starts with attacks of migraine with aura at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually occurring between 40 and 50 years of age which are sometimes associated with severe mood disturbances. The disease leads about two decades later to death after a variable period of subcortical dementia associated with pseudobulbar palsy and urinary incontinence. In one given family, the severity of the clinical presentation varies among the affected subjects. MRI is always abnormal in symptomatic subjects. It shows more or less confluent hypersignals on T2-weighted images in white-matter and basal ganglia and hyposignals on T1-weighted images in the same regions corresponding to small infarcts. These signal abnormalities are even observed a long time before the onset of clinical manifestations as they are present in totally asymptomatic young family members. Histologic studies show a widespread palor of white-matter and multiple small infarcts in the white-matter and basal ganglia underlaid by a small artery disease of the brain. Electron microscopy studies show that the media of the white-matter and leptomeningeal small arteries is thickened by a granular, eosinophilic and non-amyloid material of undetermined origin close to the smooth muscle cells. These ultrastructural wall abnormalities have been observed in other arteries, particularly in muscular and skin arteries. Mutations of Notch3 gene located on chromosome 19 are responsible for the disease. The diagnosis should be discussed in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders of subcortical dementia whenever associated with MRI signal abnormalities in white-matter and basal ganglia. PMID:9684003
Chabriat, H; Joutel, A; Vahedi, K; Iba-Zizen, M T; Tournier-Lasserve, E; Bousser, M G
Transperitoneal Laparoscopic Nephrectomy for Autosomal Dominant Polycystic Kidney Disease
Objective: This study focuses on laparoscopic nephrectomy for autosomal dominant polycystic kidney disease (ADPKD). Material and Methods: We retrospectively reviewed 21 consecutive patients who had previously undergone laparoscopy between 2007 and 2010. Data were compared to that obtained from 19 consecutive patients who had open surgery between 2004 and 2007. Clinical parameters, operative data, perioperative mortality, postoperative complications, and length of hospital stay were compared using ?2 and Student t tests for qualitative and quantitative variables, respectively. Results: Nephrectomy is usually performed to create space for renal transplantation (81% and 79%, respectively). Operating time was longer with the laparoscopic approach (180 min vs. 128 min, P = .001). Blood loss was comparable in the 2 groups (154 vs. 222 ml, P = .359) but 3 patients were transfused in the open surgery group as compared with 1 patient in the laparoscopic group. No conversion was needed. There was a trend in the laparoscopic group with respect to lower consumption of analgesics in the postoperative period (P = .06). Delay to transit recovery (2.1 d vs 4.1 d, P < .001) and hospital stay (5.2 d vs. 8.28 d, P = .002) were significantly decreased in the laparoscopic group. The interval from surgery to renal transplantation was lower in patients operated on laparoscopically (3.1 vs. 12 mo). Complications occurred in 33% of the patients in the laparoscopic group as compared with 68% in the open surgery group (P = .22). Severe complications were less frequent in the laparoscopic group (9.5% vs. 37%, P = .04). Conclusion: Laparoscopic nephrectomy is a feasible and safe procedure for ADPKD. Morbidity is significantly reduced compared with the open approach.
Delreux, Arnaud; Mathieu, Romain; Patard, Jean-Jacques; Vigneau, Cecile; Rioux-Leclercq, Nathalie; Bensalah, Karim
PRPF4 mutations cause autosomal dominant retinitis pigmentosa.
Retinitis pigmentosa (RP), a disease characterized by progressive loss of photoreceptors, exhibits significant genetic heterogeneity. Several genes associated with U4/U6-U5 triple small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome have been implicated in autosomal dominant RP (adRP). HPrp4, encoded by PRPF4, regulates the stability of U4/U6 di-snRNP, which is essential for continuous splicing. Here, we identified two heterozygous variants in PRPF4, including c.-114_-97del in a simplex RP patient and c.C944T (p.Pro315Leu), which co-segregates with disease phenotype in a family with adRP. Both variants were absent in 400 unrelated controls. The c.-114_-97del, predicted to affect two transcription factor binding sites, was shown to down-regulate the promoter activity of PRPF4 by a luciferase assay, and was associated with a significant reduction of PRPF4 expression in the blood cells of the patient. In fibroblasts from an affected individual with the p.Pro315Leu variant, the expression levels of several tri-snRNP components, including PRPF4 itself, were up-regulated, with altered expression pattern of SC35, a spliceosome marker. The same alterations were also observed in cells over expressing hPrp4(Pro315Leu), suggesting that they arose as a compensatory response to a compromised splicing mechanism caused by hPrp4 dysfunction. Further, over expression of hPrp4(Pro315Leu), but not hPrp4(WT), triggered systemic deformities in wild-type zebrafish embryos with the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced. We conclude that mutations of PRPF4 cause RP via haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP. PMID:24419317
Chen, Xue; Liu, Yuan; Sheng, Xunlun; Tam, Pancy O S; Zhao, Kanxing; Chen, Xuejuan; Rong, Weining; Liu, Yani; Liu, Xiaoxing; Pan, Xinyuan; Chen, Li Jia; Zhao, Qingshun; Vollrath, Douglas; Pang, Chi Pui; Zhao, Chen
Biochemische Besonderheiten und Unterschiede der autosomal dominant und autosomal recessiv vererbten Myotonia congenita
Zusammenfassung Das Fettsäuremuster der Muskelphosphatide von Patienten mit autosomal dominanter Myotonia congenita unterscheidet sich sehr stark von dem der Patienten mit autosomal recessiver Myotonia congenita und von Muskelgesunden. Zunahme der Palmitinsäure (C 16:0), Stearinsäure (C 18:0), Eikosadiensäure (C 20:2) und 5,8,11 Eikosatriensäure (C 20:3) sowie Abnahme der Ölsäure (C 18:1), Linolsäure (C 18:2) und der Arachidonsäure (C 20:4) wurden gefunden.
E. Kuhn; D. Seiler
Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years' Experience
Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. Design, setting, participants, and measurements This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. Results Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m2) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: ?2.1 versus ?0.71 ml/min per 1.73 m2/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m2/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = ?0.21, P < 0.01). Conclusion ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.
Higashihara, Eiji; Chapman, Arlene B.; Grantham, Jared J.; Bae, Kyongtae; Watnick, Terry J.; Horie, Shigeo; Nutahara, Kikuo; Ouyang, John; Krasa, Holly B.; Czerwiec, Frank S.
Hageman Trait (Factor XII Deficiency): A Probable Second Genotype Inherited as an Autosomal Dominant Characteristic
A family is described in which Hage- Immunologic studies suggested that man trait appeared to be inherited in the molecular defect was similar to an autosomal dominant manner in that of the autosomal recessive form contrast to previously reported families and consisted of deficiency of anti- in which the disorder behaves as an gens related to Hageman factor. autosomel recessive
Bruce Bennett; James B. Holt; Harold R. Roberts
Pathways of caspase-mediated apoptosis in autosomal-dominant polycystic kidney disease (ADPKD)
Pathways of caspase-mediated apoptosis in autosomal-dominant polycystic kidney disease (ADPKD).BackgroundWe have recently demonstrated an increase in apoptosis in Han:SPRD rat kidneys with autosomal-dominant polycystic kidney disease (ADPKD). Caspase-3 and caspase-7 are major mediators of apoptosis. There are two pathways of caspase-3 and caspase-7–mediated apoptosis: (1) the "extrinsic" pathway involving the death receptor Fas, Fas ligand (FasL), and caspase-8 and (2)
YUNXIA TAO; JUN KIM; MELINDA STANLEY; ZHIBIN HE; SARAH FAUBEL; Robert W. Schrier; Charles L. Edelstein
A gene for autosomal dominant congenital nystagmus localizes to 6p12
Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.
Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K. [Johns Hopkins Hospital, Baltimore, MD (United States)] [and others] [Johns Hopkins Hospital, Baltimore, MD (United States); and others
Congenital hepatic fibrosis in a child with autosomal dominant polycystic kidney disease.
The association of congenital hepatic fibrosis (CHF) with autosomal recessive polycystic kidney disease (ARPKD) is well known and occurs in approximately 50% of cases. However the association of CHF with autosomal dominant polycystic kidney disease (ADPKD) is less well known and less well documented. We report a child with neonatal onset of hypertension due to ADPKD who later develops portal hypertension due to CHF in childhood. A review of this rare association follows. PMID:19248702
Kanaheswari, Y; Hamzaini, A H; Wong, S W
Autosomal Dominant Growth Hormone Deficiency Disrupts Secretory Vesicles in Vitro and in Vivo in Transgenic Mice
Autosomal dominant GH deficiency type II (IGHDII) is often associated with mutations in the human GH gene (GH1) that give rise to products lacking exon-3 (exon3hGH). In the het- erozygous state, these act as dominant negative mutations that prevent the release of human pituitary GH (hGH). To determine the mechanisms of these dominant negative ef- fects, we used a combination
Evidence of clinical and genetic heterogeneity in autosomal dominant congenital cerulean cataracts.
Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chromosome 17q24 and the other on chromosome 22q11.2-q12.2, which includes the beta-B2 crystallin (CRYBB2) candidate gene. Using polymorphic markers in these regions (D17S802, D17S836, D17S1806 and CRYBB2, D22S258) for linkage analysis, we excluded these loci in a large Moroccan family presenting with an unusual form of ADCC with early onset of lens opacities and rapid evolution. This finding confirms the clinical and genetic heterogeneity of autosomal dominant congenital cerulean cataracts. PMID:12567263
Hilal, Latifa; Nandrot, Emeline; Belmekki, Mohamed; Chefchaouni, Mohamed; El Bacha, Siham; Benazzouz, Bouchra; Hajaji, Yassir; Gribouval, Olivier; Dufier, Jean; Abitbol, Marc; Berraho, Amina
Bovine Polledness - An Autosomal Dominant Trait with Allelic Heterogeneity
The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ?381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations.
Medugorac, Ivica; Seichter, Doris; Graf, Alexander; Russ, Ingolf; Blum, Helmut; Gopel, Karl Heinrich; Rothammer, Sophie; Forster, Martin; Krebs, Stefan
Autosomal Dominant Polycystic Kidney Disease: New Treatment Options and How to Test Their Efficacy
Autosomal dominant polycystic kidney disease (ADPKD) represents a slowly progressing cystic kidney disorder which evolves into end-stage renal disease in the majority of patients. Currently, there are no established treatments to retard the progression of the disease, but several promising therapeutic options are being tested in ongoing clinical trials. An inherent dilemma for the investigation of therapies in ADPKD is
Rudolf P. Wüthrich; Andreas L. Serra; Andreas D. Kistler
Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by localized autono- mous cellular proliferation, fluid accumulation within the cysts, and intraparenchymal fibrosis of the kidney. Little is known about the cyst fluid's protein composition. We hypothesized that the complex collection of cyst fluid proteins (cyst fluid proteome) plays a major role in cyst formation\\/maintenance and contains yet unknown diagnostic and
Xianyin Lai; Robert L. Bacallao; Bonnie L. Blazer-Yost; David Hong; Stephen B. Mason; Frank A. Witzmann
Olfactory Identification Deficits in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
Background\\/Aims: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations of the Notch 3 gene. Olfactory identification deficits are present in a number of neurodegenerative disorders. However, olfaction has not been investigated in CADASIL. The aim of the present study was to assess olfactory identification in CADASIL and to determine whether there
Jung Seok Lee; Jay Chol Choi; Sa-Yoon Kang; Ji-Hoon Kang; Sang Hun Lee; Jeong Hong Kim; SangYun Kim
Familial Cutaneous Malignant Melanoma: Autosomal Dominant Trait Possibly Linked to the Rh Locus
Segregation and linkage analyses were undertaken in families with multiple cases of cutaneous malignant melanoma (CMM) and a recently-described melanoma precursor, the dysplastic nevus syndrome (DNS). Clinical and laboratory data, including 23 genetic markers, were collected on 401 members of 14 high-risk kindreds. Pedigree analysis was compatible with an autosomal dominant mode of inheritance for the familial CMM trait. Although
Mark H. Greene; Lynn R. Goldin; Wallace H. Clark; Everett Lovrien; Kenneth H. Kraemer; Margaret A. Tucker; David E. Elder; Mary C. Fraser; Shirley Rowe
Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency
ERIC Educational Resources Information Center
Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…
Dale, Russell C.; Melchers, Anna; Fung, Victor S. C.; Grattan-Smith, Padraic; Houlden, Henry; Earl, John
Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever
Background: Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is a rare autosomal dominant inflammatory disorder with episodic symptoms precipitated by exposure to cold. Objective: The goal of this study was to formulate clinical diagnostic criteria for FCAS in a large cohort in whom the diagnosis of FCAS was supported by genetic linkage to chromosome 1q44. Methods:
Hal M. Hoffman; Alan A. Wanderer; David H. Broide
Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine
Autosomal dominant polycystic kidney disease (ADPKD) is a frequent cause of kidney failure; however, urinary biomarkers for the disease are lacking. In a step towards identifying such markers, we used multidimensional-multinuclear nuclear magnetic resonance (NMR) spectroscopy with support vector machine-based classification and analyzed urine specimens of 54 patients with ADPKD and slightly reduced estimated glomerular filtration rates. Within this cohort,
Wolfram Gronwald; Matthias Klein; Raoul Zeltner; Bernd-Detlef Schulze; Stephan W Reinhold; Markus Deutschmann; Ann-Kathrin Immervoll; Carsten A Böger; Bernhard Banas; Kai-Uwe Eckardt; Peter J Oefner
Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.
Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened and occasionally are bifid. The feet are similarly but less severely affected. We have performed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage to the same region on chromosome 9 (combined multipoint maximum LOD score 8.69 with marker D9S257). The 16-cM disease interval is defined by recombinations with markers D9S1680 and D9S1786. These two families share an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provides strong evidence that the English families have the same ancestral mutation, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in this family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22.
Oldridge, M; Temple, I K; Santos, H G; Gibbons, R J; Mustafa, Z; Chapman, K E; Loughlin, J; Wilkie, A O
WNT5A Mutations in Patients with Autosomal Dominant Robinow Syndrome
Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown, however the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development, and that proper formation and growth of these structures is sensitive to variations in WNT5A function.
Person, Anthony D.; Beiraghi, Soraya; Sieben, Christine M.; Hermanson, Spencer; Neumann, Ann N.; Robu, Mara E.; Schleiffarth, J. Robert; Billington, Charles J.; van Bokhoven, Hans; Hoogeboom, J.; Mazzeu, Juliana F.; Petryk, Anna; Schimmenti, Lisa A.; Brunner, Han G.; Ekker, Stephen C.; Lohr, Jamie L.
[A case of autosomal dominant, pure form spastic paraplegia with thinning of the corpus callosum].
Autosomal dominant hereditary spastic paraplegia (HSP) is genetically classified into three types, all of which are characterized by insidiously progressive spasticity of the lower extremities. Patients with a complicated form of autosomal recessive HSP associated with hypoplasia of the corpus callosum have been reported by Iwabuchi et al. Here we report a 64-year-old patient with a pure form of autosomal dominant HSP with thinning of the corpus callosum. He had been well until 12 years of age, when spasticity and weakness of the lower extremities began to develop. His symptoms gradually worsened and he had difficulty in walking at the age of 44. When he was 56 years old, he visited our hospital. Eleven family members over five generations have been affected, and anticipation, i.e., an apparent decrease in age of onset, has been observed. On admission, he had mild cataracts, equinovarus and pes cavus, and neurological examination revealed spastic paraplegia. However, the intelligence test was normal, and nystagmus, ataxia of the extremities, involuntary movement, orthostatic hypotension or urinary disturbance was not observed. Trinucleotide repeat diseases, such as Huntington's disease, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, Machado-Joseph disease and dentatorubral-pallidoluysian atrophy, were excluded by DNA analysis. Brain MRI at the age of 64 revealed marked thinning of the corpus callosum. We considered this patient had a pure form of HSP. However, thinning of the corpus callosum has never been reported in autosomal dominant HSP. PMID:9805990
Tomiyasu, H; Hayashi, R; Watanabe, R; Honda, M; Yoshii, F
WNT5A mutations in patients with autosomal dominant Robinow syndrome.
Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia, and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown; however, the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here, we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function. PMID:19918918
Person, Anthony D; Beiraghi, Soraya; Sieben, Christine M; Hermanson, Spencer; Neumann, Ann N; Robu, Mara E; Schleiffarth, J Robert; Billington, Charles J; van Bokhoven, Hans; Hoogeboom, Jeannette M; Mazzeu, Juliana F; Petryk, Anna; Schimmenti, Lisa A; Brunner, Han G; Ekker, Stephen C; Lohr, Jamie L
[Temperature-sensitive autosomal dominant lethal mutations in Drosophila melanogaster induced by ethylmethane sulfonate].
Cold- and heat-sensitive dominant autosome and recessive sex-linked lethals were scored using C(1)RM, y; vg bw; e ss tester stock. The frequencies of heat-sensitive mutations were 1.43, 0.30, 0.07% and of cold-sensitive ones were 0.39, 0.16 and 0.09% in the 1-st, 2-nd and 3-rd chromosomes, respectively. For the first time, dominant cold-sensitive lethals were obtained in chromosome 3. The data from genetic analysis point to the fact that penetrance of such mutations strongly depends on the genetic background. That may be the reason, why they were not obtained using some of the balancer-3 chromosomes. Also, "cryptic" dominant autosome mutants were found which were not conditional but only revealed in the F2 generation. Their possible origin as gonado-somatic mosaics is discussed. PMID:6407896
Miasniankina, E N; Generalova, M V; Mitrofanov, V G
Autosomal dominant polycystic kidney disease with diffuse proliferative glomerulonephritis - an unusual association: a case report and review of the literature
INTRODUCTION: Autosomal dominant polycystic kidney disease is an inherited disorder that is characterized by the development and growth of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g\\/24 hours in autosomal dominant polycystic kidney disease, and an association of nephrotic syndrome with this condition is considered rare. There are only anecdotal case reports
Sanjay D'Cruz; Rajdeep Singh; Harsh Mohan; Ravinder Kaur; Ranjana Walker Minz; Vinay Kapoor; Atul Sachdev
A Mutation in Autosomal Dominant Myotonia Congenita Affects Pore Properties of the Muscle Chloride Channel
Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl- channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl- channel (hClC-1) expressed in a mammalian
Christoph Fahlke; Carol L. Beck; Alfred L. George
Exon Splice Enhancer Mutation (GH-E32A) Causes Autosomal Dominant Growth Hormone Deficiency
Context and Objective: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing. Design, Setting, and Patients: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon
Vibor Petkovic; Didier Lochmatter; James Turton; Peter E. Clayton; Peter J. Trainer; Mehul T. Dattani; Andree Eble; Iain C. Robinson; Christa E. Fluck; Primus E. Mullis
Familial arachnoid cysts in association with autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder well-known for its association with intracranial aneurysms. Recently, intracranial arachnoid cysts have also been reported to be associated with ADPKD. We describe a father and daughter who each has a posterior fossa arachnoid cyst and asymptomatic ADPKD. To our knowledge, this is the first report of familial occurrence of arachnoid cysts in association with ADPKD. PMID:12093994
Alehan, Füsun Korkmaz; Gürakan, Berkan; A?ildere, Muhte?em
Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model
Background Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion,\\u000a resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported\\u000a to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the\\u000a early stage of ADPKD is necessary to clarify its
Takafumi Toyohara; Takehiro Suzuki; Yasutoshi Akiyama; Daisuke Yoshihara; Yoichi Takeuchi; Eikan Mishima; Koichi Kikuchi; Chitose Suzuki; Masayuki Tanemoto; Sadayoshi Ito; Shizuko Nagao; Tomoyoshi Soga; Takaaki Abe
Distal arthrogryposis with autosomal dominant inheritance and reduced penetrance in females: the Gordon syndrome.
A family is reported in which camptodactyly, club foot, pectus excavatum and undescended testes are transmitted as an autosomal dominant with reduced penetrance and variable expressivity, affecting 13 members through five generations. Penetrance is more reduced in females than in males and asymptomatic carriers are always females. Similar findings were previously described in two other families reported by Gordon et al. (1962) and Halal & Fraser (1979). PMID:8370149
Ioan, D M; Belengeanu, V; Maximilian, C; Fryns, J P
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes
Alexander Zimprich; Saskia Biskup; Petra Leitner; Peter Lichtner; Matthew Farrer; Sarah Lincoln; Jennifer Kachergus; Mary Hulihan; Ryan J. Uitti; Donald B. Calne; A. Jon Stoessl; Ronald F. Pfeiffer; Nadja Patenge; Iria Carballo Carbajal; Peter Vieregge; Friedrich Asmus; Bertram Müller-Myhsok; Dennis W. Dickson; Thomas Meitinger; Tim M. Strom; Zbigniew K. Wszolek; Thomas Gasser
An autosomal dominant syndrome with 'acromegaloid' features and thickened oral mucosa.
A previously undescribed autosomal dominant syndrome has been observed in a large kindred with affected relatives spanning at least five generations. The phenotype is highly variable and appears to show complete penetrance. Affected persons have a progressively coarse, acromegaloid-like facial appearance and thickening of the lips and intraoral mucosa. The differences are discussed between this syndrome and three rather similar syndromes, pachydermoperiostosis, the Ascher syndrome, and multiple neuroma syndrome. Images
Hughes, H E; McAlpine, P J; Cox, D W; Philipps, S
Outcome of kidney transplantation in autosomal dominant medullary cystic kidney disease type 1
Background. Autosomal dominant medullary cystic kidney disease (ADMCKD) is an inherited, distinct, chronic, tubulointerstitial, cystic-type nephropathy, often described together with juvenile nephronoph- thisis as a single disease complex (NPH-MCD). However, since the recent localization of two genes responsible for ADMCKD, namely MCKD1 and MCKD2, ADMCKD has gained independent status. Unfortunately, there appears to be a distinct lack of up-to-date information
Christoforos Stavrou; C. Constantinou Deltas; Tasos C. Christophides; Alkis Pierides
Phenotypic Characterization of 3 Families With Autosomal Dominant Retinitis Pigmentosa Due to Mutations in KLHL7
Objective To characterize the visual phenotype caused by mutations in the BTB-Kelch protein, KLHL7, responsible for the RP42 form of autosomal dominant retinitis pigmentosa (RP). Methods Comprehensive ophthalmic testing included visual acuity, static visual field, kinetic visual field, dark adaptometry, full-field electroretinography, spectral-domain optical coherence tomography, and fundus photography. Longitudinal visual function data (range, 15–27 years) were available for some of the affected individuals. Results We report a phenotypic assessment of 3 unrelated families, each harboring different KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). The fundi showed classic signs of RP. Best-corrected visual acuity was 20/50 or better in at least one eye up to age 65 years Static and kinetic visual fields showed concentric constriction to central 10° to 20° by age 65 years; 2 patients with Goldmann perimetry exhibited bilateral visual field retention in the far periphery. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years. Conclusions Mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors. Full-field electroretinographic findings, including recovery kinetics, are consistent with those observed in other forms of autosomal dominant RP. Clinical Relevance The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). Strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing may guide mutation screening in autosomal dominant RP.
Wen, Yuquan; Locke, Kirsten G.; Klein, Martin; Bowne, Sara J.; Sullivan, Lori S.; Ray, Joseph W.; Daiger, Stephen P.; Birch, David G.; Hughbanks-Wheaton, Dianna K.
Palmoplantar keratoderma, nail dystrophy, and hereditary motor and sensory neuropathy: an autosomal dominant trait.
Autosomal dominant inheritance of a syndrome comprising palmoplantar keratoderma, nail dystrophy, and hereditary motor and sensory neuropathy (HMSN) was observed in three generations of one family. Nail dystrophy affected the toe and fingernails; it was present at birth or developed during early childhood. Palmoplantar keratoderma became apparent in later childhood. Each subject with nail dystrophy and keratoderma also had clinical or electrophysiological evidence of axonal neuropathy. Images
Tolmie, J L; Wilcox, D E; McWilliam, R; Assindi, A; Stephenson, J B
Human Genome and Diseases: Review Molecular basis of autosomal-dominant polycystic kidney disease
Autosomal-dominant polycystic kidney dis- ease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1 and polycystin-2, the proteins encoded by these two genes. While poly- cystin-1 may mediate the contact among
A. R. Gallagher; S. Hidaka; R. Witzgall
The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52
Jared J. Grantham
Autosomal dominant brachyolmia in a large Swedish family: Phenotypic spectrum and natural course.
Autosomal dominant brachyolmia (Type 3, OMIM #113500) belongs to a group of skeletal dysplasias caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) gene, encoding a Ca(++) -permeable, non-selective cation channel. The disorder is characterized by disproportionate short stature with short trunk, scoliosis and platyspondyly. The phenotypic variability and long-term natural course remain inadequately characterized. The purpose of this study was to describe a large Swedish family with brachyolmia type 3 due to a heterozygous TRPV4 mutation c.1847G>A (p.R616Q) in 11 individuals. The mutation has previously been detected in another family with autosomal dominant brachyolmia [Rock et al., 2008]. Review of hospital records and patient assessments indicated that clinical symptoms of brachyolmia became evident by school age with chronic pain in the spine and hips; radiographic changes were evident earlier. Growth was not affected during early childhood but deteriorated with age in some patients due to increasing spinal involvement. Affected individuals had a wide range of subjective symptoms with chronic pain in the extremities and the spine, and paresthesias. Our findings indicate that autosomal dominant brachyolmia may be associated with significant long-term morbidity, as seen in this family. © 2014 Wiley Periodicals, Inc. PMID:24677493
Grigelioniene, Giedre; Geiberger, Stefan; Horemuzova, Eva; Moström, Eva; Jäntti, Nina; Neumeyer, Lo; Aström, Eva; Nordenskjöld, Magnus; Nordgren, Ann; Mäkitie, Outi
A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes.
Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50-60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts. PMID:22552817
Dufke, Claudia; Schlipf, Nina; Schüle, Rebecca; Bonin, Michael; Auer-Grumbach, Michaela; Stevanin, Giovanni; Depienne, Christel; Kassubek, Jan; Klebe, Stephan; Klimpe, Sven; Klopstock, Thomas; Otto, Susanne; Poths, Sven; Seibel, Andrea; Stolze, Henning; Gal, Andreas; Schöls, Ludger; Bauer, Peter
A Novel ?B-Crystallin Mutation Associated with Autosomal Dominant Congenital Lamellar Cataract
Purpose To identify the mutation and the underlying mechanism of cataractogenesis in a five-generation autosomal dominant congenital lamellar cataract family. Methods Nineteen mutation hot spots associated with autosomal dominant congenital cataract have been screened by PCR-based DNA sequencing. Recombinant wild-type and mutant human ?B-crystallin were expressed in Escherichia coli and purified to homogeneity. The recombinant proteins were characterized by far UV circular dichroism, intrinsic tryptophan fluorescence, Bis-ANS fluorescence, multiangle light-scattering, and the measurement of chaperone activity. Results A novel missense mutation in the third exon of the ?B-crystallin gene (CRYAB) was found to cosegregate with the disease phenotype in a five-generation autosomal dominant congenital lamellar cataract family. The single-base substitution (G?A) results in the replacement of the aspartic acid residue by asparagine at codon 140. Far UV circular dichroism spectra indicated that the mutation did not significantly alter the secondary structure. However, intrinsic tryptophan fluorescence spectra and Bis-ANS fluorescence spectra indicated that the mutation resulted in alterations in tertiary and/or quaternary structures and surface hydrophobicity of ?B-crystallin. Multiangle light-scattering measurement showed that the mutant ?B-crystallin tended to aggregate into a larger complex than did the wild-type. The mutant ?B-crystallin was more susceptible than wild-type to thermal denaturation. Furthermore, the mutant ?B-crystallin not only lost its chaperone-like activity, it also behaved as a dominant negative which inhibited the chaperone-like activity of wild-type ?B-crystallin. Conclusions These data indicate that the altered tertiary and/or quaternary structures and the dominant negative effect of D140N mutant ?B-crystallin underlie the molecular mechanism of cataractogenesis of this pedigree.
Liu, Yizhi; Zhang, Xinyu; Luo, Lixia; Wu, Mingxing; Zeng, Ruiping; Cheng, Gang; Hu, Bin; Liu, Bingfen; Liang, Jack J.; Shang, Fu
Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa
Inherited retinal diseases are a common cause of visual impairment in children and young adults, often resulting in severe loss of vision in later life. The most frequent form of inherited retinopathy is retinitis pigmentosa (RP), with an approximate incidence of 1 in 3,500 individuals worldwide1,2. RP is characterized by night blindness and progressive degeneration of the midperipheral retina, accompanied by bone spicule-like pigmentary deposits and a reduced or absent electroretinogram (ERG). The disease process culminates in severe reduction of visual fields or blindness. RP is genetically heterogeneous, with autosomal dominant, autosomal recessive and X-linked forms. Here we have identified two mutations in a novel retina-specific gene from chromosome 8q that cause the RP1 form of autosomal dominant RP in three unrelated families. The protein encoded by this gene is 2,156 amino acids and its function is currently unknown, although the amino terminus has similarity to that of the doublecortin protein, whose gene (DCX) has been implicated in lissencephaly in humans17. Two families have a nonsense mutation in codon 677 of this gene (Arg677stop), whereas the third family has a nonsense mutation in codon 679 (Gln679stop). In one family, two individuals homozygous for the mutant gene have more severe retinal disease compared with heterozygotes.
Sullivan, Lori S.; Heckenlively, John R.; Bowne, Sara J.; Zuo, Jian; Hide, Winston A.; Gal, Andreas; Denton, Michael; Inglehearn, Chris F.; Blanton, Susan H.; Daiger, Stephen P.
TBC1D24 Mutation Causes Autosomal-Dominant Nonsyndromic Hearing Loss.
Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal-dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole-exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders. PMID:24729539
Azaiez, Hela; Booth, Kevin T; Bu, Fengxiao; Huygen, Patrick; Shibata, Seiji B; Shearer, A Eliot; Kolbe, Diana; Meyer, Nicole; Black-Ziegelbein, E Ann; Smith, Richard J H
Seizure semiology in autosomal dominant epilepsy with auditory features, due to novel LGI1 mutations.
Mutations in LGI1 are found in 50% of families with autosomal dominant epilepsy with auditory features (ADEAF). In ADEAF, family members have predominantly lateral temporal lobe seizures but mesial temporal lobe semiology may also occur. We report here three families with novel LGI1 mutations (p.Ile82Thr, p.Glu225*, c.432-2_436del). Seven affected individuals reported an auditory aura and one a visual aura. A 10-year old boy described a cephalic aura followed by an unpleasant taste and oral automatisms without auditory, visual or psychic features. PMID:24206907
Sadleir, Lynette G; Agher, Dahbia; Chabrol, Elodie; Elkouby, Léa; Leguern, Eric; Paterson, Sarah J; Harty, Rosie; Bellows, Susannah T; Berkovic, Samuel F; Scheffer, Ingrid E; Baulac, Stéphanie
Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1-2q13.
In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations. PMID:14755735
Neilson, Derek E; Feiler, Heidi S; Wilhelmsen, Kirk C; Lynn, Audrey; Eiben, Robert M; Kerr, Douglas S; Warman, Matthew L
[Massive inferior vena cava thrombosis in a patient with autosomal dominant polycystic hepatorenal disease].
We report a 68-year-old man with autosomal dominant polycystic kidney disease, who developed multiple venous thromboses (inferior vena cava, left renal vein and iliofemoral veins) caused by local compression of the intrahepatic inferior vena cava by hepatic cysts. To our knowledge this is the first reported case of inferior vena cava thrombosis caused by hepatic cysts compression. Doppler ultrasound, computed tomography, and magnetic resonance imaging were effective in documenting the venous thromboses and the underlying lesions non-invasively. Long-term anticoagulation was an efficient and safe treatment. PMID:11987689
Peces, R; Gil, F; Costero, O; Pobes, A
Recurrent Acute Pancreatitis and Cholangitis in a Patient with Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis.
Yazdanpanah, Kambiz; Manouchehri, Navid; Hosseinzadeh, Elinaz; Emami, Mohammad Hassan; Karami, Mehdi; Sarrami, Amir Hossein
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with severe factor XII deficiency.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited adult-onset microangiopathy caused by missense mutations in the Notch3gene on chromosome 19. However, common vascular risk factors may additionally modify clinical expression and progression of the disease. The role of various prothrombotic factors has also been implied. We report a case of a middle-aged man with typical clinical, neuroimaging and histological features of CADASIL, but with notably prolonged activated partial thromboplastin time. Hematological investigations revealed severe clotting Factor XII deficiency. This case illustrates that the occurrence of vascular risk factors should not be overlooked in patients with CADASIL. PMID:19934572
Sternic, Nadezda; Pavlovic, Aleksandra; Miljic, Predrag; Bajcetic, Milos; Lackovic, Maja; Lackovic, Vesna
67Ga SPECT/CT Accurately Localized Recurrent Hepatic Cyst Infection in Patients With Autosomal Dominant Polycystic Kidney Disease.
Hepatic pyocyst is a rare but potentially life-threatening complication of autosomal dominant polycystic kidney disease. With extensive hepatic cystic disease, localization of a pyocyst and targeted aspiration or drainage is often a diagnostic challenge. Two patients with autosomal dominant polycystic kidney disease and recurrent gram-negative sepsis were imaged with Ga SPECT/CT for investigation of an infective source. In both patients, imaging accurately localized infected pyocysts and guided percutaneous drainage and further management. PMID:24662650
Ayesa, Sally Louise; Gradinscak, Denis J; Schembri, Geoff P
Bilateral hand-assisted laparoscopic nephrectomy for autosomal dominant polycystic kidney disease using a single midline handport incision
Objectives. To present one of the first known series of bilateral, transperitoneal laparoscopic nephrectomy for autosomal dominant polycystic kidney disease using a hand-assisted technique by way of a single, midline HandPort incision. Synchronous, bilateral nephrectomy for autosomal dominant polycystic kidney disease is an infrequently performed procedure, with only a few reports using laparoscopy.Methods. We retrospectively reviewed the charts of 4
Michael A Jenkins; J. Jason Crane; Larry C Munch
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.
We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation. PMID:11440988
Pesch, U E; Leo-Kottler, B; Mayer, S; Jurklies, B; Kellner, U; Apfelstedt-Sylla, E; Zrenner, E; Alexander, C; Wissinger, B
A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family
Purpose To identify the genetic defects associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods Clinical data were collected, and the phenotypes of the affected members in this family were recorded by slit-lamp photography. Genomic DNA was isolated from peripheral blood. Mutations were screened in cataract-associated candidate genes through polymerase chain reaction (PCR) analyses and sequencing. Structural models of the wild-type and mutant ?B-crystallin were generated and analyzed by SWISS-MODEL. Results Mutation screening identified only one heterozygous G?A transition at nucleotide 32 in the first exon of ?B-crystallin (CRYAB), resulting in an amino acid change from arginine to histidine at codon 11 (R11H). This mutation segregated in all available affected family members but was not observed in any of the unaffected persons of the family. The putative mutation disrupted a restriction site for the enzyme, Fnu4HI, in the affected family members. The disruption, however, was not found in any of the randomly selected ophthalmologically normal individuals or in 40 unrelated senile cataract patients. Computer-assisted prediction suggested that this mutation affected the biochemical properties as well as the structure of ?B-crystallin. Conclusions These results supported the idea that the novel R11H mutation was responsible for the autosomal dominant nuclear congenital cataract in this pedigree.
Chen, Qiang; Ma, Junjie; Yan, Ming; Mothobi, Maneo Emily; Liu, Yuanyuan
Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation
Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-D7S553-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. The authors propose the name SHSF2 for this second locus. 34 refs., 4 figs., 1 tab.
Palmer, S.E.; Wijsman, E.M.; Stephens, K.; Evans, J.P. (Univ. of Washington School of Medicine, Seattle, WA (United States)); Scherer, S.W.; Tsui, L.C. (Univ. of Toronto (Canada)); Kukolich, M. (Genetic Screening and Counseling Service, Denton, TX (United States))
Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis
The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif–containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLC?1, the identification of mutations that may alter the putative INF2–IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.
Boyer, Olivia; Benoit, Genevieve; Gribouval, Olivier; Nevo, Fabien; Tete, Marie-Josephe; Dantal, Jacques; Gilbert-Dussardier, Brigitte; Touchard, Guy; Karras, Alexandre; Presne, Claire; Grunfeld, Jean-Pierre; Legendre, Christophe; Joly, Dominique; Rieu, Philippe; Mohsin, Nabil; Hannedouche, Thierry; Moal, Valerie; Gubler, Marie-Claire; Broutin, Isabelle; Mollet, Geraldine
A novel nonsense mutation in CRYGC is associated with autosomal dominant congenital nuclear cataracts and microcornea
Purpose To report the identification of a novel nonsense mutation in CRYGC in a Chinese family with autosomal dominant congenital nuclear cataracts and microcornea. Methods We investigated a four-generation Chinese family with six members affected with nuclear cataracts and microcornea. The family resides in a relatively isolated region of northern China. Genomic DNA was isolated from blood leucocytes, genotyping was performed using more than 100 microsatellite markers for the known cataract candidate gene loci, and LOD scores were calculated using the LINKAGE programs. Mutations were detected by DNA sequence analysis of the candidate genes. Results Evidence for linkage was detected at marker D2S325 (LOD score [Z]=2.29, recombination fraction [?]=0.0), which closely flanks the ?-crystallin gene cluster (CRYGA-CRYGD) on chromosome 2q32.3-q35. Direct sequencing of the candidate CRYGA-CRYGD gene cluster revealed a c.470G>A transversion in exon 3 of CRYGC, which cosegregated with cataracts in the family and was not observed in 100 normal controls. This single nucleotide change was predicted to introduce a translation stop codon at tryptophan 157 (W157X). Conclusions The present study has identified a novel nonsense mutation in CRYGC associated with autosomal dominant cataracts and microcornea in a Chinese family. Our finding expands the spectrum of CRYGC mutations associated with congenital cataract and confirms the role of ?-crystallin in the pathogenesis of congenital nuclear cataracts.
Zhang, Lu; Fu, Songbin; Ou, Yangshan; Zhao, Tingting; Su, Yunjuan
A new novel mutation in FBN1 causes autosomal dominant Marfan syndrome in a Chinese family
Purpose Screening of mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). Methods It has been reported that FBN1 mutations account for approximately 90% of Autosomal Dominant MFS. FBN1 mutations were analyzed in a Chinese family of 36 members including 13 MFS patients. The genomic DNAs from blood leukocytes of the patients and their relatives were isolated and the entire coding region of FBN1 was amplified by PCR. The sequence of FBN1 was dertermined with an ABI 3100 Genetic Analyzer. Results A previously unreported the missense mutation G214S (caused by a 640 A?G heterozygous change) in FBN1 was identified in the Chinese family. The mutation was associated with the disease phenotype in patients, but not detected in their relatives or in the 100 normal controls. Conclusions This is the first report of molecular characterization of FBN1 in the MFS family of Chinese origin. Our results expand the spectrum of FBN1 mutations causing MFS and further confirm the role of FBN1 in the pathogenesis of MFS. Direct sequencing of the mutation in FBN1 may be used for diagnosis of MFS.
Dong, Jiamei; Bu, Juan; Du, Wei; Li, Yuan; Jia, Yanlei; Li, Jianchang; Meng, Xiaoli; Yuan, Minghui; Peng, Xiaojuan; Zhou, Aimin
Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.
To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.
Campion, D; Dumanchin, C; Hannequin, D; Dubois, B; Belliard, S; Puel, M; Thomas-Anterion, C; Michon, A; Martin, C; Charbonnier, F; Raux, G; Camuzat, A; Penet, C; Mesnage, V; Martinez, M; Clerget-Darpoux, F; Brice, A; Frebourg, T
Mutation Spectra in Autosomal Dominant and Recessive Retinitis Pigmentosa in Northern Sweden
Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of retinitis pigmentosa (RP) is 1/3500 worldwide, however, in northern Sweden it is 1/2000 due to limited migration and a 'founder' effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern Sweden. Several novel mutations unique for this region were found. In an autosomal recessive form of RP, Bothnia dystrophy caused by mutations in the RLBP1 gene, bi-allelic mutations R234W, M226K and compound heterozygosity, M226K+R234W was detected. In dominant form of RP mapped to 19q13.42 a 59 kb genomic deletion including the PRPF31 and three other genes was found. These data provide additional information on the molecular mechanisms of RP evolvement and in the future might be useful in development of therapeutic strategies. Identification of the disease-causing mutations allowed introducing molecular genetic testing of the patients and their families into the clinical practice.
Kohn, Linda; Burstedt, Marie; Daiger, Stephen; Sandgren, Ola
A Neonatal Case of Autosomal Dominant Hypoparathyroidism without Mutation of the CASR Gene
We experienced a case of familial hypoparathyroidism with an autosomal dominant pattern of transmission and performed molecular analysis of the calcium-sensing receptor (CASR) gene. The patient was a female neonate, born by cesarean section at term because of breech presentation. Her mother had been diagnosed with idiopathic hypoparathyroidism at the age of 9 yr and had been receiving vitamin D treatment since then. At birth, the patient's serum calcium concentration was 8.4 mg/dl, but it fell to 4.0 mg/dl on the fifth day after birth. Furthermore, her serum intact PTH level was inappropriately low, while hyperphosphatemia and hypomagnesemia were found. She was diagnosed with familial hypoparathyroidism, and was immediately started on oral administration of 1?(OH)D3 (0.1 µg/kg/day) and continuous intravenous infusion of 8.5% calcium gluconate. Additionally, trichlormethiazide was administered because of elevated urinary calcium/creatinine (Ca/Cr) ratio. Her serum calcium concentration gradually improved thereafter. In this case, autosomal dominant hypocalcemia (ADH) due to abnormality in the CASR gene was clinically suspected, but DNA sequencing analysis revealed no mutation of the CASR gene in either the patient or her mother. This result suggests that the patient's hypoparathyroidism may have been caused by abnormality in a gene other than CASR.
Miyata, Ichiro; Yoshikawa, Hideki; Kurokawa, Naokiyo; Kanno, Kei-ichi; Hayashi, Yoshihiro; Eto, Yoshikatsu
Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis.
The common autosomal dominant form of hereditary spherocytosis (HS) has been genetically linked to defects of the erythroid ankyrin gene in a few families; however, the frequency of ankyrin deficiency and its relationship to red blood cell (RBC) spectrin content are unknown. To test these questions, we measured RBC spectrin and ankyrin by radioimmunoassay in 39 patients from 20 families with dominant HS. Normal RBCs contained 242,000 +/- 20,500 spectrin heterodimers and 124,500 +/- 11,000 ankyrins per cell. In dominant HS, RBC spectrin and ankyrin ranged from about 40% to 100% of normal and were continuously distributed. Measurements in the same patient on different occasions were reproducible (+/- 5% to 10%) and RBCs from affected members of a kindred contained similar amounts of spectrin and ankyrin (+/- 3% to 4%). Spectrin and ankyrin levels were almost always less than the assay controls, but were less than the normal range in only 75% and 80% of kindreds, respectively. Remarkably, the degree of RBC spectrin and ankyrin deficiency was very similar in 19 of 20 HS kindreds. One otherwise typical family differed, with marked ankyrin deficiency (45% of control) and a relatively mild spectrin deficit (81%). We conclude that most patients with dominant HS have combined ankyrin and spectrin deficiency and that the two proteins are usually about equally deficient, suggesting that defects in ankyrin expression, ankyrin stability, or ankyrin band 3 (AE1) interactions may be common in dominant HS. PMID:8219186
Savvides, P; Shalev, O; John, K M; Lux, S E
Screening for mutations in rhodopsin and peripherin/RDS in patients with autosomal dominant retinitis pigmentosa
Mutations in rhodopsin account for approximately 30% of all cases of autosomal dominant retinits pigmentosa (adRP) and mutations in peripherin/RDS account for an additional 5% of cases. Also, mutations in rhodopsin can cause autosomal recessive retinitis pigmentosa and mutations in peripherin/RDS can cause dominant macular degeneration. Most disease-causing mutations in rhodopsin and peripherin/RDS are unique to one family or, at most, to a few families within a limited geographic region, though a few mutations are found in multiple, unrelated families. To further determine the spectrum of genetic variation in these genes, we screened DNA samples from 134 unrelated patients with retinitis pigmentosa for mutations in both rhodopsin and peripherin/RDS using SSCP followed by genomic sequencing. Of the 134 patients, 86 were from families with apparent adRP and 48 were either isolated cases or were from families with an equivocal mode of inheritance. Among these patients we found 14 distinct rhodopsin mutations which are likely to cause retinal disease. Eleven of these mutations were found in one individual or one family only, whereas the Pro23His mutation was found in 14 {open_quotes}unrelated{close_quotes}individuals. The splice-site mutation produces dominant disease though with highly variable expression. Among the remaining patients were found 6 distinct peripherin/RDS mutations which are likely to cause retinal disease. These mutations were also found in one patient or family only, except the Gly266Asp mutation which was found in two unrelated patients. These results confirm the expected frequency and broad spectrum of mutations causing adRP.
Rodriguez, J.A.; Gannon, A.M.; Daiger, S.P. [Univ. of Texas HSC, Houston, TX (United States)] [and others
Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease.
Mutations in protein kinase C substrate 80K-H (PRKCSH), encoding for the protein hepatocystin, cause autosomal dominant polycystic liver disease (PCLD), which is clinically characterized by the presence of multiple liver cysts. PCLD has been documented in families from Europe (Netherlands, Belgium, Finland) as well as from the United States. In this article, we report results from extensive mutational analysis of the PRKCSH gene in a group of 14 PCLD families and 65 singleton cases of Dutch and Finnish descent with multiple simple liver cysts. We identified PRKCSH mutations in 12 families and in 3 sporadic cases. In 8 of 10 Finnish families we detected the 1437+2delTG splice-site mutation. In Dutch families, we found 2 other mutations that affect correct splicing of PRKCSH: 292+1 G>C (2 families) and 1338-2 A>G (1 family). In another Dutch family, we detected a novel deletion (374-375delAG) in exon 6, predicting an abnormal shortened protein. Investigation of the carrier haplotypes identified a common founder chromosome in unrelated individuals in each of the 3 identified splice-site mutations. In 2 Finnish families with dominantly inherited PCLD, and in 62 of 65 sporadic cases with multiple simple liver cysts, we failed to demonstrate any PRKCSH mutation. This corroborates the notion that autosomal dominant PCLD is genetically heterogeneous. In conclusion, we propose that, on the basis of our results, genetic screening for PRKCSH gene mutations should be limited to patients either with a positive family history for PCLD or who have severe polycystic liver disease. PMID:15057895
Drenth, Joost P H; Tahvanainen, Esa; te Morsche, Rene H M; Tahvanainen, Pia; Kääriäinen, Helena; Höckerstedt, Krister; van de Kamp, Jiddeke M; Breuning, Martijn H; Jansen, Jan B M J
Linkage of the late onset autosomal dominant familial spastic paraplegia (DFSPII) to chromosome 2p markers
Pure familial spastic paraplegias (FSP) is a neurodegenerative disease characterized by spasticity of lower limbs. FSP in inherited as an autosomal dominant (DFSP) or an autosomal recessive (RFSP) trait. DFSP has been classified into early onset (DFSPI) and late onset (DFSPII) based on the mean age of onset in families. A locus for RFSP has been mapped to chromosome 8, while a locus for DFSPI has been mapped to chromosome 14q. Genetic locus heterogeneity was observed in both of these forms. The location of DFSPII locus (or loci) is unknown. We collected DNA samples from 81 individuals including 26 affecteds from three DFSPII families (9998, 840, 581). The mean age of onset of systems was 26.5, 42.5, and 35.2 years, respectively. We first tested 156 DNA markers distributed throughout the human 22 autosomes with family 9998 and positive lod scores were obtained with chromosome 2p markers D2S174 (Z({theta})=2.93 at {theta}=0.00), D2S146 (Z({theta})=1.03 at {theta}=0.00) and D2S177 (Z({theta})=1.04 at {theta}=0.00). Analysis of the 2 additional families confirmed the linkage with a peak lod score of Z({theta})=4.62 at {theta}=0.105 with D2S174. The multipoint linkage analysis using the map D2S175-10cM-D2S174-14cM-D2DS177 suggested that the DFSPII locus most likely maps between D2S174 and D2S177 with Z({theta})=6.11. There was no evidence in our data supporting genetic locus heterogeneity for the DFSPII.
Hentati, A.; Wasserman, B.; Siddique, T. [Northwestern Univ. Medical School, Chicago, IL (United States)] [and others
Autosomal dominant familial spastic paraplegia; Linkage analysis and evidence for linkage to chromosome 2p
Familial spastic paraplegia (FSP) is a degenerative disorder of the motor system characterized by progressive weakness and spasticity of the lower limbs. Little is known about the pathophysiology of this disorder. FSP can be inherited as an autosomal dominant (AD), autosomal recessive, or X-linked trait. We have undertaken linkage analysis for a group of 36 AD FSP families from which we have collected blood samples from 427 individuals, including 148 affected individuals. Typing of polymorphic markers has allowed us to exclude more than 50% of the genome. Recently, linkage for AD FSP to a locus on chromosome 14q was reported. Our AD FSP kindreds were tested for linkage to markers spanning the 20 cM region between D14S69 and D14S66; however, we were not able to establish linkage for any of our families to chromosome 14. Lod scores suggestive of linkage for some AD FSP kindreds have been obtained for markers on chromosome 2p. We have tested seven polymorphic markers spanning the region between D2S405 and D2S177. Our highest aggregate lod score, including all families tested, was obtained at the locus D2S352: 2.4 at 20 cM. Results from HOMOG analysis for linkage heterogeneity will be reported.
Figlewicz, D.A. [Univ. of Rochester, NY (United States); Dube, M.P.; Rouleau, G.A. [McGill Univ., Montreal (Canada)] [and others
Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts
Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33–35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction ?=0) was obtained for marker D2S2208 near the ?-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts.
Nandrot, E; Slingsby, C; Basak, A; Cherif-Chefchaoun..., M; Benazzouz, B; Hajaji, Y; Boutayeb, S; Gribouval, O; Arbogast, L; Berraho, A; Abitbol, M; Hilal, L
The prevalence of "pure" autosomal dominant hereditary spastic paraparesis in the island of Ireland
Objectives: Hereditary spastic paraparesis (HSP) is clinically and genetically heterogeneous. "Pure" autosomal dominant (AD) HSP is most common and eight genetic loci are identified to date. Previous studies have included autosomal recessive and sporadic cases in prevalence calculations. This study aimed to determine the prevalence and features of pure ADHSP in the island of Ireland. Methods: Index cases were identified from a 5 year survey of all adult and paediatric neurologists, clinical geneticists, hospital records, and hospital inpatient enquiry system data in Ireland, north and south. Families were examined by two neurologists and classified as affected or unaffected according to specific criteria. The prevalence date was set at 1 June 2000 and the midyear population estimate for the previous year was 5.436 million. Results: Eighty two patients with pure ADHSP and a further 12 obligate carriers from 19 families were identified. In total 69 patients with pure ADHSP were alive and resident in Ireland at the prevalence date. Twenty nine per cent of these were asymptomatic but with signs of paraparesis. Conclusions: The prevalence of ADHSP in Ireland to estimated to be 1.27/100 000 population. The high proportion of asymptomatic cases and obligate carriers means that this condition is likely to be underdiagnosed.
McMonagle, P; Webb, S; Hutchinson, M
Octreotide reduces hepatic, renal and breast cystic volume in autosomal-dominant polycystic kidney disease.
A 43-year-old woman with autosomal-dominant polycystic kidney disease (ADPKD) received octreotide for 12 months, and this was associated with a 6.3% reduction in liver volume, an 8% reduction in total kidney volume and stabilization of renal function. There was also a reduction of cyst size in fibrocystic disease of breast. These data suggest that the cyst fluid accumulation in different organs from patients with ADPKD is a dynamic process which can be reversed by octreotide. This is the first report of a case of simultaneous reduction in hepatic, renal and breast cystic volume with preservation of renal function in a patient with ADPKD receiving octreotide. PMID:20449653
Peces, Ramón; Cuesta-López, Emilio; Peces, Carlos; Pérez-Dueńas, Virginia; Vega-Cabrera, Cristina; Selgas, Rafael
[Seminal vesicle cysts and infertility in autosomal dominant polycystic kidney disease].
Autosomal dominant polycystic kidney disease (ADPKD) is a systemic hereditary disorder characterized by bilateral diffuse renal cysts. Extrarenal involvement is a well known manifestation of ADPKD. Cysts in the liver, pancreas, lung, spleen, oesophagus, ovary, testis, epididymis, prostate, thyroid, bladder, uterus, brain, paraespinal, and seminal vesicle have also been described. The occurrence of seminal vesicle cysts is often unrecognised. We report here a man with seminal vesicle cysts and azoospermia associated with ADPKD. Seminal vesicle cysts are not uncommon in ADPKD and in some cases it is associated with infertility. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively. Studies evaluating fertility in patients with seminal vesicle cysts and ADPKD are needed. PMID:15789541
Peces, R; Venegas, J L
Polymorphisms in the human autosomal dominant polycystic kidney disease 2 (PKD2) gene.
Three polymorphisms of the PKD2 (MIM 173910) gene in patients with autosomal dominant polycystic kidney disease are reported: (1) a substitution from ATT (isoleucine) to GTT (valine) at codon 452; (2) a substitution from CGG (arginine) to CAG (glutamine) at codon 848; and (3) a substitution from G to A in intron 4 of the gene. The minor allelic frequencies of codon 452 and intron 4 in the Korean population were estimated to be 0.03 and 0.32, respectively. Although the codon 848 substitution was not observed in 45 unrelated healthy Korean people, the substitution did not cosegregate with the disease phenotype, suggesting that this was a rare, non-deleterious alteration. PMID:10369752
Kim, U K; Shin, J H; Lee, K B; Kim, S H; Chae, J J; Hong, S S; Jin, D K; Namkoong, Y; Lee, C C
Autosomal dominant polycystic kidney disease with ectopic unilateral multicystic dysplastic kidney
Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. In most cases, ADPKD similarly affects bilateral kidneys. Case presentation Among the 605 ADPKD patients that were followed up by our center, we identified two male patients with unilateral ADPKD. The cases were remarkable because the patients also had ectopia and multicystic dysplasia in the contralateral kidney, which are generally sporadic disease conditions. Both patients tested positive for polycystic kidney disease 1 mutation, but negative for hepatocyte nuclear factor 1 beta mutation. Moreover, the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings. Both patients had started a long-term hemodialysis in their 40s. Conclusion Anatomical and genetic abnormality in patients with ADPKD may be more frequent and complex than previously believed. The compensatory capacity in patients with ADPKD is fragile, and missing one kidney could accelerate the deterioration of renal function.
Recurrent acute pancreatitis and cholangitis in a patient with autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis. PMID:23543834
Yazdanpanah, Kambiz; Manouchehri, Navid; Hosseinzadeh, Elinaz; Emami, Mohammad Hassan; Karami, Mehdi; Sarrami, Amir Hossein
Retinal findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil).
We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. CADASIL is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for CADASIL and are typically seen only on electron microscopy. Although CADASIL is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient. PMID:11274696
Robinson, W; Galetta, S L; McCluskey, L; Forman, M S; Balcer, L J
Outcomes of renal transplantation in patients with autosomal dominant polycystic kidney disease: a nationwide longitudinal study.
Renal transplantation in patients with autosomal dominant polycystic kidney disease (ADPKD) is a medical and surgical challenge. Detailed longitudinal epidemiological studies on large populations are lacking and it is mandatory to care better for these patients. The success of such a project requires the development of a validated epidemiological database. Herein, we present the results of the largest longitudinal study to date on renal transplant in patients with ADPKD. The 15-year outcomes following renal transplantation of 534 ADPKD patients were compared with 4779 non-ADPKD patients. This comprehensive, longitudinal, multicenter French study was performed using the validated database, DIVAT (Données Informatisées et VAlidées en Transplantaion). We demonstrate that renal transplantation in ADPKD is associated with better graft survival, more thromboembolic complications, more metabolic complications, and increased incidence of hypertension, whereas the prevalence of infections is not increased. This study provides important new insights that could lead to a better care for renal transplant patients with ADPKD. PMID:21352383
Jacquet, Antoine; Pallet, Nicolas; Kessler, Michčle; Hourmant, Maryvonne; Garrigue, Valérie; Rostaing, Lionel; Kreis, Henri; Legendre, Christophe; Mamzer-Bruneel, Marie-France
Autosomal dominant lateral temporal epilepsy (ADLTE): absence of chromosomal rearrangements in LGI1 gene.
Mutations of leucine-rich, glioma inactivated 1 (LGI1) gene are found in about half of the families with autosomal dominant lateral temporal epilepsy (ADLTE). More recently a LGI1 heterozygous microdeletion was found in a single ADLTE family, suggesting that submicroscopic chromosomal abnormalities should be investigated in cases negative for LGI1 mutations. This study examines whether microdeletions and duplications of the LG1 gene occurred in eight ADLTE families and 20 sporadic patients that were negative for LGI1 mutations. Multiplex ligation-dependent probe amplification (MLPA) was applied to detect potential deletions and duplications of LGI1 gene. In all patients, MLPA analysis did not reveal any pathogenic changes in the LGI1 gene. Chromosomal rearrangements involving the LGI1 gene were not identified in our series of familial or sporadic LTE. These results further illustrate the considerable genetic heterogeneity for ADLTE, despite the relatively homogeneous clinical picture. There are as yet undiscovered mechanisms underlying ADLTE. PMID:24315022
Manna, Ida; Mumoli, Laura; Labate, Angelo; Citrigno, Luigi; Ferlazzo, Edoardo; Aguglia, Umberto; Quattrone, Aldo; Gambardella, Antonio
DNA Testing For Live Kidney Donors At Risk For Autosomal Dominant Polycystic Kidney Disease*
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by age-dependent growth of kidney cysts with end-stage renal disease developing in about 50% of affected individuals. Living donors from ADPKD families are at risk for developing ADPKD and may be excluded from renal donation if the diagnosis cannot be conclusively ruled out. Radiographic imaging may be adequate to screen for kidney cysts in most at-risk donors but may fail to identify affected individuals younger than 40 or older individuals from families with mild disease. In this paper we report a strategy that incorporates genetic testing in the evaluation of live kidney donors at risk for ADPKD whose disease status cannot be established with certainty on the basis of imaging studies alone. We show that DNA diagnostics can be used to enhance safe donation for certain living donor candidates at risk for ADPKD.
Huang, Edmund; Samaniego-Picota, Millie; McCune, Thomas; Melancon, Joseph K.; Montgomery, Robert A.; Ugarte, Richard; Kraus, Edward; Womer, Karl; Rabb, Hamid; Watnick, Terry
Autosomal dominant nemaline myopathy caused by a novel alpha-tropomyosin 3 mutation.
Nemaline myopathy (NM) is a genetically and clinically heterogenous muscle disorder, which is myopathologically characterized by nemaline bodies. Mutations in six genes have been reported to cause NM: Nebulin (NEB Pelin 1999), alpha-skeletal muscle actin (ACTA1 Nowak 1999), alpha-slow tropomyosin (TPM3 Laing 1995), beta-tropomyosin (TPM2 Donner 2002), slow troponin T (TNNT1 Johnston 2000) and cofilin 2 (CFL2 Agrawal 2007). The majority of cases are due to mutation in NEB and ACTA1. We report on the clinical, myopathological and muscle MRI findings in a German family with autosomal dominant NM due to a novel pathogenic TPM3 mutation (p.Ala156Thr). PMID:20012312
Kiphuth, I C; Krause, S; Huttner, H B; Dekomien, G; Struffert, T; Schröder, R
Identification and biochemical analysis of a novel APOB mutation that causes autosomal dominant hypercholesterolemia
Patients with autosomal dominant hypercholesterolemia (ADH) have a high risk of developing cardiovascular disease that can be effectively treated using statin drugs. Molecular diagnosis and family cascade screening is recommended for early identification of individuals at risk, but up to 40% of families have no mutation detected in known genes. This study combined linkage analysis and exome sequencing to identify a novel variant in exon 3 of APOB (Arg50Trp). Mass spectrometry established that low-density lipoprotein (LDL) containing Arg50Trp APOB accumulates in the circulation of affected individuals, suggesting defective hepatic uptake. Previously reported mutations in APOB causing ADH have been located in exon 26. This is the first report of a mutation outside this region causing this phenotype, therefore, more extensive screening of this large and highly polymorphic gene may be necessary in ADH families. This is now feasible due to the high capacity of recently available sequencing platforms.
Thomas, Ellen R A; Atanur, Santosh S; Norsworthy, Penny J; Encheva, Vesela; Snijders, Ambrosius P; Game, Laurence; Vandrovcova, Jana; Siddiq, Afshan; Seed, Mary; Soutar, Anne K; Aitman, Timothy J
Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1)
The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6 prox). This region is 750 kb long and has been cloned. The authors have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. They report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Their results favor a location of the PKD1 gene in the proximal part of the candidate region. 25 refs., 1 fig., 4 tabs.
Snarey, A. (Imperial Cancer Research Fund, London (United Kingdom)); Thomas, S.; Harris, P.C. (Institute of Molecular Medicine, Oxford (United Kingdom)); Schneider, M.C. (Brigham and Women's Hospital, Boston, MA (United States)); Pound, S.E.; Wright, A.F. (Western General Hospital, Edinburgh (United Kingdom)); Barton, N.; Somlo, S.; Germino, G.G.; Reeders, S.T. (and others)
Novel Single-Base Deletional Mutation in Major Intrinsic Protein (MIP) in Autosomal Dominant Cataract
PURPOSE To further elucidate the cataract phenotype, and identify the gene and mutation for autosomal dominant cataract (ADC) in an American family of European descent (ADC2) by sequencing the major intrinsic protein gene (MIP), a candidate based on linkage to chromosome 12q13. DESIGN Observational case series and laboratory experimental study. METHODS We examined two at-risk individuals in ADC2. We PCR-amplified and sequenced all four exons and all intron-exon boundaries of the MIP gene from genomic and cloned DNA in affected members to confirm one variant as the putative mutation. RESULTS We found a novel single deletion of nucleotide (nt) 3223 (within codon 235) in exon four, causing a frameshift that alters 41 of 45 subsequent amino acids and creates a premature stop codon. CONCLUSIONS We identified a novel single base pair deletion in the MIP gene and conclude that it is a pathogenic sequence alteration.
Geyer, David D.; Spence, M. Anne; Johannes, Meriam; Flodman, Pamela; Clancy, Kevin P.; Berry, Rebecca; Sparkes, Robert S.; Jonsen, Matthew D.; Isenberg, Sherwin J.; Bateman, J. Bronwyn
Familial third-fourth pharyngeal pouch syndrome with apparent autosomal dominant transmission.
A family is presented in which both siblings and their father had evidence of third-fourth pharyngeal pouch syndrome (DiGeorge syndrome). All three individuals had hypocalcemia and unusual facies. Both infants had truncus arteriosus. One infant had evidence of impaired cell-mediated immunity; the father had a relatively decreased number of T-lymphocytes. The syndrome is uncommon, most cases being isolated, and familial presentations are even rarer. Two recent reports described several affected individuals who also had partial deletions of chromosome 22. Chromosome banding studies in our family were normal. Thus our family demonstrates an autosomal dominant pattern of inheritance, although it cannot be proved that this is a single gene defect. We propose that inasmuch as the presentation of the syndrome is quite varied, thorough family investigation including high-resolution cytogenetic analysis is necessary. Familial cases may be more common and require genetic counseling. PMID:6737148
Rohn, R D; Leffell, M S; Leadem, P; Johnson, D; Rubio, T; Emanuel, B S
Autosomal dominant distal spinal muscular atrophy: an Italian family not linked to 12q24 and 7p14.
Distal spinal muscular atrophy is genetically heterogeneous, as sporadic cases and both autosomal dominant and recessive inheritance have been described. An autosomal dominant distal spinal muscular atrophy with upper limb predominance has been mapped to chromosome 7p, and more recently, an autosomal dominant distal spinal muscular atrophy with lower limb predominance has been linked to chromosome 12q24. We describe a four generation Italian family with autosomal dominant distal spinal muscular atrophy starting between 8 and 30 years with weakness and atrophy of distal leg muscles. The older patients also presented sensorineural deafness. We performed genetic linkage analysis with microsatellite markers D12S366, D12S349, D12S86, D12S321, D12S1612, D12S1349, D12S342, PLA2A on chromosome 12q24 and D7S516, D7S2496, D7S632, D7S2252 on chromosome 7p14. No support for linkage to chromosome 12q24 and 7p14 was found in our family, confirming a genetic heterogeneity within autosomal dominant distal spinal muscular atrophy. PMID:11731281
De Angelis, M V; Gatta, V; Stuppia, L; Passamonti, L; Gambi, D; Uncini, A
Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q
Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.
Fink, J.K.; Wu, C.T.B.; Jones, S.M.
A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance. PMID:22781092
Nicolaou, Paschalis; Cianchetti, Carlo; Minaidou, Anna; Marrosu, Giovanni; Zamba-Papanicolaou, Eleni; Middleton, Lefkos; Christodoulou, Kyproula
A novel nonsense mutation in CRYBB1 associated with autosomal dominant congenital cataract
Purpose To identify the molecular defect underlying an autosomal dominant congenital nuclear cataract in a Chinese family. Methods Twenty-two members of a three-generation pedigree were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. All members were genotyped with polymorphic microsatellite markers adjacent to each of the known cataract-related genes. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. Individuals were screened for presence of a mutation by restriction fragment length polymorphism (RFLP) analysis. Results Linkage analysis identified a maximum LOD score of 3.31 (recombination fraction [?]=0.0) with marker D22S1167 on chromosome 22, which flanks the ?-crystallin gene cluster (CRYBB3, CRYBB2, CRYBB1, and CRYBA4). Sequencing the coding regions and the flanking intronic sequences of these four candidate genes identified a novel, heterozygous C?T transition in exon 6 of CRYBB1 in the affected individuals of the family. This single nucleotide change introduced a novel BfaI site and was predicted to result in a nonsense mutation at codon 223 that changed a phylogenetically conserved amino acid to a stop codon (p.Q223X). RFLP analysis confirmed that this mutation co-segregated with the disease phenotype in all available family members and was not found in 100 normal unrelated individuals from the same ethnic background. Conclusions This study has identified a novel nonsense mutation in CRYBB1 (p.Q223X) associated with autosomal dominant congenital nuclear cataract.
Yang, Juhua; Zhu, Yihua; Gu, Feng; He, Xiang; Cao, Zongfu; Li, Xuexi; Tong, Yi
Calcification simulating infection in congenital brachydactyly.
Two cases of idiopathic soft tissue calcification occurring in the vestigial fingers of infants with congenital brachydactyly are reported. Both patients presented with acute local inflammation simulating infection and responded well to simple excision of the calcium deposits. PMID:3944438
Jones, F E
Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa.
Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene, resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP. Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases. PMID:9701253
Lewin, A S; Drenser, K A; Hauswirth, W W; Nishikawa, S; Yasumura, D; Flannery, J G; LaVail, M M
Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: A clinical masquerader.
Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature. PMID:24813031
Jain, Rajendra S; Prakash, Swayam; Raghavendra, B S; Nagpal, Kadam; Handa, Rahul
[From gene to disease; hepatocystin and autosomal dominant polycystic liver disease].
Polycystic liver disease (PCLD, MIM 174050) is a dominantly inherited condition characterised by the presence in the liver of multiple cysts of biliary epithelial origin. It must be distinguished from autosomal dominant polycystic kidney disease type 1 (ADPKD-1, MIM 173900) and type 2 (ADPKD-2). Both disorders may be complicated by polycystic liver disease, but renal involvement is absent in PCLD. PCLD is often asymptomatic, but if symptoms arise, they are usually due to the mass effect of cysts. The phenotype is more severe in females and correlates with the number of pregnancies or estrogen use. The gene for PCLD has been assigned to chromosome 19p13.2-13.1. Two separate large-scale positional cloning efforts have managed to identify PRKCSH as the gene underlying PCLD. Up to now, all mutations found in PRKCSH introduce stopcodons in the m-RNA, resulting in premature termination of translation to protein. This suggests a loss of function of the encoding protein. The protein, designated by us as hepatocystin, is predicted to be localised in the endoplasmic reticulum. Multiple biological roles have been suggested for hepatocystin, such as a substrate for phosphorylation by protein kinase C, binding to advanced glycation endproducts, and a function as the non-catalytic beta-subunit of glucosidase-II. The role of hepatocystin in PCLD, however, remains to be elucidated. PMID:12894465
Jansen, J B M J; Morsche, R H M Te; Drenth, J P H
Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy
Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long–chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long–chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.
Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D.; Kabir, Nabila; Mandal, Nawajes A.; Brush, Richard S.; Anderson, Robert E.
Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy.
Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology. PMID:23509295
Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D; Kabir, Nabila; Mandal, Nawajes A; Brush, Richard S; Anderson, Robert E
Mutation conferring apical-targeting motif on AE1 exchanger causes autosomal dominant distal RTA.
Mutations in SLC4A1 that mislocalize its product, the chloride/bicarbonate exchanger AE1, away from its normal position on the basolateral membrane of the ?-intercalated cell cause autosomal dominant distal renal tubular acidosis (dRTA). We studied a family exhibiting dominant inheritance and defined a mutation (AE1-M909T) that affects the C terminus of AE1, a region rich in potential targeting motifs that are incompletely characterized. Expression of AE1-M909T in Xenopus oocytes confirmed preservation of its anion exchange function. Wild-type GFP-tagged AE1 localized to the basolateral membrane of polarized MDCK cells, but AE1-M909T localized to both the apical and basolateral membranes. Wild-type AE1 trafficked directly to the basolateral membrane without apical passage, whereas AE1-M909T trafficked to both cell surfaces, implying the gain of an apical-targeting signal. We found that AE1-M909T acquired class 1 PDZ ligand activity that the wild type did not possess. In summary, the AE1-M909T mutation illustrates the role of abnormal targeting in dRTA and provides insight into C-terminal motifs that govern normal trafficking of AE1. PMID:22518001
Fry, Andrew C; Su, Ya; Yiu, Vivian; Cuthbert, Alan W; Trachtman, Howard; Karet Frankl, Fiona E
A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy.
A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree. PMID:22382025
Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan; Dai, Xianning; Zhou, Huihui; Dong, Xujie; Liu, Xiao-Ling; Guan, Min-Xin
Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa
Purpose. To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE). Methods. DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed. Results. Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies. Conclusions. The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.)
Sullivan, Lori S.; Bowne, Sara J.; Reeves, Melissa J.; Blain, Delphine; Goetz, Kerry; NDifor, Vida; Vitez, Sally; Wang, Xinjing; Tumminia, Santa J.; Daiger, Stephen P.
Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India
Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India. Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2. Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described. Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.
Sinha, K; Worth, P; Jha, D; Sinha, S; Stinton, V; Davis, M; Wood, N; Sweeney, M; Bhatia, K
Fibular hypoplasia and complex brachydactyly (Du Pan syndrome) in an inbred Pakistani kindred.
A Pakistani kindred comprising 7 generations contained 7 men and 2 women with fibular hypoplasia and complex brachydactyly (syn: Du Pan syndrome). Analysis of the pedigree is strongly suggestive of autosomal recessive inheritance. The average inbreeding coefficient (F) for the affected persons was found to be significantly greater than that for unaffected persons in the pedigree and consanguineous loops could account for all affected persons being homozygous for the abnormal allele. PMID:2363425
Ahmad, M; Abbas, H; Wahab, A; Haque, S
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): Diagnostic skin biopsy changes determined by electron microscopy
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial vascular disorder associated with migraines, recurrent ischemic strokes, and early-onset multiinfarct dementia. The diagnosis of CADASIL is made ultrastructurally by finding characteristic granular, electron-dense, osmiophilic material attached to vascular smooth muscle cells. These changes have been found in brain, skeletal muscle, nerve, and skin. We describe a
John S. Walsh; Charles Perniciaro; James F. Meschia
Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study
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Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…
Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent
Concurrent Renal Cell Carcinoma and Central Nervous System Lymphoma in a Patient with Autosomal Dominant Polycystic Kidney Disease
Objective: To report an unusual case of synchronous renal cell carcinoma and CNS lymphoma in a patient with autosomal dominant polycystic kidney disease (ADPKD). Case Presentation and Intervention: A 58-year-old woman presented with progressive right hemiparesis of 2 months' duration. A brain CT scan revealed multiple enhanced lesions in the basal ganglia and the right occipital lobe. CNS lymphoma was
Ming-Yang Chang; Yu-Ming Chen; Yung-Cheng Chen; Ya-Chung Tian; Ji-Tseng Fang; Chih-Wei Yang
Disparate Effects of Roscovitine on Renal Tubular Epithelial Cell Apoptosis and Senescence: Implications for Autosomal Dominant Polycystic Kidney Disease
Background\\/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can
Jin-Young Park; See-Hyoung Park; Robert H. Weiss
Bilateral persistent hyperplastic primary vitreous: an Egyptian family supporting a rare autosomal dominant inheritance.
Persistent hyperplastic primary vitreous (PHPV) is an idiopathic congenital malformation confined to the eye that has no obvious cause and that is usually unilateral and sporadic. The clinical features of the classic PHPV syndrome include white, vascularized tissue covering some or all of the posterior surface of the lens; centrally dragged ciliary processes; secondary glaucoma caused by swelling of the lens or caused by contracture of the retrolental tissue, with anterior shifting of the lens-iris diaphragm; extensive intravitrael hemorrhaging; persistence of the hyaloid artery; and occasionally retinal detachment. In the present study we describe a patient with bilateral PHPV not associated with other diseases. Normal developmental milestones were reported. Family pedigree analysis revealed a similarly affected father, grandfather, 2 aunts, 1 paternal uncle and a grand uncle with 2 affected daughters. On examination the height, weight and skull circumference were on the 5th percentile. Bilateral B&A eye scan ultrasonography (B mode is two dimensional brightness mode ultrasonography, while A mode is one dimensional where echoes are represented by spikes of variable amplitude and timing) of both the patient and the father revealed a picture suggestive of persistent hyperplastic primary vitreous. Cytogenetics study by conventional culture technique using the CTG banding technique revealed a normal male karyotype 46, XY for both of them. Review of the London Dysmorphology Data Base (LDDB), OMIM, and recent medical literature revealed that this case to our knowledge represents the second report supporting autosomal dominant inheritance of PHPV not associated with other anomalies. PMID:17375531
Galal, A H; Kotoury, A I S; Azzab, A A
Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.
The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis. PMID:18587396
Rock, Matthew J; Prenen, Jean; Funari, Vincent A; Funari, Tara L; Merriman, Barry; Nelson, Stanley F; Lachman, Ralph S; Wilcox, William R; Reyno, Soraya; Quadrelli, Roberto; Vaglio, Alicia; Owsianik, Grzegorz; Janssens, Annelies; Voets, Thomas; Ikegawa, Shiro; Nagai, Toshiro; Rimoin, David L; Nilius, Bernd; Cohn, Daniel H
Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia
The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature1. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1–12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4?-phorbol 12,13-didecanoate (4?PDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.
Rock, Matthew J; Prenen, Jean; Funari, Vincent A; Funari, Tara L; Merriman, Barry; Nelson, Stanley F; Lachman, Ralph S; Wilcox, William R; Reyno, Soraya; Quadrelli, Roberto; Vaglio, Alicia; Owsianik, Grzegorz; Janssens, Annelies; Voets, Thomas; Ikegawa, Shiro; Nagai, Toshiro; Rimoin, David L; Nilius, Bernd; Cohn, Daniel H
New insights into the pathogenesis of autosomal dominant cutis laxa with report of five ELN mutations
Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28–34 of the ELN gene in 5 probands with ADCL features and found 5 de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5) and c.2124del25 (CL-6). Four probands (CL-1, -2, -3, -6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF?) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF? signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.
Callewaert, Bert; Renard, Marjolijn; Hucthagowder, Vishwanathan; Albrecht, Beate; Hausser, Ingrid; Blair, Edward; Dias, Cristina; Albino, Alice; Wachi, Hiroshi; Sato, Fumiaki; Mecham, Robert P.; Loeys, Bart; Coucke, Paul J.; De Paepe, Anne; Urban, Zsolt
Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.
The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major non-collagenous components of the tectorial membrane. Recently, the gene encoding mouse alpha-tectorin (Tecta) was mapped to a region of mouse chromosome 9, which shows evolutionary conservation with human chromosome 11q (ref. 3), where linkage was found in two families, one Belgian (DFNA12; ref. 4) and the other, Austrian (DFNA8; unpublished data), with autosomal dominant non-syndromic hearing impairment. We determined the complete sequence and the intron-exon structure of the human TECTA gene. In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA. These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment. PMID:9590290
Verhoeven, K; Van Laer, L; Kirschhofer, K; Legan, P K; Hughes, D C; Schatteman, I; Verstreken, M; Van Hauwe, P; Coucke, P; Chen, A; Smith, R J; Somers, T; Offeciers, F E; Van de Heyning, P; Richardson, G P; Wachtler, F; Kimberling, W J; Willems, P J; Govaerts, P J; Van Camp, G
Myeloperoxidase-antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis in autosomal dominant polycystic kidney disease
Background Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder that is characterized by the development of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g/day, and ADPKD is rarely associated with nephrotic syndrome or rapidly progressive glomerulonephritis (RPGN). To date, myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CrGN) has not been reported in a patient with ADPKD. Case presentations We report two cases of MPO-ANCA positive ADPKD. A 60-year-old Japanese woman (case 1) and a 54-year-old Japanese woman (case 2) presented with RPGN featuring severe proteinuria and microscopic hematuria. In both patients percutaneous needle biopsy of the kidney revealed MPO-ANCA-associated CrGN with a paucity of glomerular immunoglobulin staining. Each patient received intravenous methylprednisolone for 3 days, followed by oral prednisolone. Case 1 showed gradual improvement and has not progressed to end-stage renal disease (ESRD), but case 2 developed ESRD requiring hemodialysis within one month despite treatment. Conclusion These are the first two reported cases of MPO-ANCA-associated CrGN in patients with ADPKD. Our experience suggests that serial measurement of the ANCA titer and renal biopsy should be considered for accurate diagnosis and appropriate treatment of ADPKD patients who present with proteinuria, hematuria, and rapid decline of renal function.
Autosomal dominant retinitis pigmentosa mutations in inosine 5?-monophosphate dehydrogenase type I disrupt nucleic acid binding
Two mutations of IMPDH1 (inosine 5?-monophosphate dehydrogenase type I), R224P and D226N, have recently been found to cause adRP (autosomal dominant retinitis pigmentosa). IMPDH1 catalyses the rate-limiting step in guanine nucleotide biosynthesis and also binds single-stranded nucleic acids. In the present paper, we report the biochemical characterization of the adRP-linked mutations, R224P and D226N, and a potentially pathogenic mutation, V268I. The adRP-linked mutations have no effect on enzyme activity, protein stability or protein aggregation. These results suggest strongly that the mutations do not affect enzyme activity in vivo and thus do not perturb the guanine nucleotide pool. The R224P mutation changes the distribution of enzyme between the nucleus and cytoplasm. This effect was not observed with the D226N mutation, so the relevance of this observation to disease is unclear. In contrast, both mutations decrease the affinity of nucleic acid binding and both fail to co-immunoprecipitate RNA. These observations suggest that nucleic acid binding provides a functional assay for adRP pathogenicity. The putative adRP-linked mutation V268I also disrupts nucleic acid binding, which suggests that this mutation is indeed pathogenic.
Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease
Background Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). Aims To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. Methods Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. Results Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. Conclusion These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.
Onori, Paolo; Mancinelli, Romina; Franchitto, Antonio; Carpino, Guido; Renzi, Anastasia; Brozzetti, Stefania; Venter, Julie; Francis, Heather; Glaser, Shannon; Jefferson, Douglas M.; Alpini, Gianfranco; Gaudio, Eugenio
Novel targets for the treatment of autosomal dominant polycystic kidney disease
Importance of the field Autosomal dominant (AD) polycystic kidney disease (PKD) is the most common life-threatening hereditary disorder. There is currently no therapy that slows or prevents cyst formation and kidney enlargement in humans. An increasing number of animal studies have advanced our understanding of molecular and cellular targets of PKD. Areas covered in the review The purpose of this review is to summarize the molecular and cellular targets involved in cystogenesis and to update on the promising therapies that are being developed and tested based on knowledge of these molecular and cellular targets. What the reader will gain Insight into the pathogenesis of PKD and how a better understanding of the pathogenesis of PKD has led to the development of potential therapies to inhibit cyst formation and/or growth and improve kidney function. Take home message The results of animal studies in PKD have led to the development of clinical trials testing potential new therapies to reduce cyst formation and/or growth. A vasopressin V2 receptor antagonist, mTOR inhibitors, blockade of the renin–angiotensin system and statins that reduce cyst formation and improve renal function in animal models of PKD are being tested in interventional studies in humans.
Belibi, Franck A; Edelstein, Charles L
Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy
We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
Ostergaard, Pia; Simpson, Michael A.; Mendola, Antonella; Vasudevan, Pradeep; Connell, Fiona C.; van Impel, Andreas; Moore, Anthony T.; Loeys, Bart L.; Ghalamkarpour, Arash; Onoufriadis, Alexandros; Martinez-Corral, Ines; Devery, Sophie; Leroy, Jules G.; van Laer, Lut; Singer, Amihood; Bialer, Martin G.; McEntagart, Meriel; Quarrell, Oliver; Brice, Glen; Trembath, Richard C.; Schulte-Merker, Stefan; Makinen, Taija; Vikkula, Miikka; Mortimer, Peter S.; Mansour, Sahar; Jeffery, Steve
Identification of a unique urinary biomarker profile in patients with autosomal dominant polycystic kidney disease.
To gain some insight into early disease progression in human autosomal dominant polycystic kidney disease (ADPKD), we analyzed the urine proteome of 41 young patients with ADPKD whose renal function was relatively preserved. Using capillary electrophoresis and mass spectrometry, we compared these results to those from age-matched healthy controls and patients with other renal diseases. There were 197 proteins with significantly altered urinary excretion; and 38 of them could be sequenced, most of which were collagen fragments. This suggests that there is high turnover of extracellular matrix proteins. Uromodulin peptides, previously implicated in tubular injury, were also found in the urine specimens. These marker proteins were found to distinguish patients from controls with a high degree of accuracy. The sensitivity and specificity of this marker set remained high in an independent validation cohort of 24 patients with ADPKD and 35 healthy controls, and even in comparisons of patients with a variety of other renal diseases or patients with kidney or bladder cancer. These findings present a potential hypothesis for the mechanisms of disease progression in ADPKD which will need to be confirmed by further studies. PMID:19340089
Kistler, Andreas D; Mischak, Harald; Poster, Diane; Dakna, Mohammed; Wüthrich, Rudolf P; Serra, Andreas L
A Novel Autosomal Dominant Inclusion Body Myopathy Linked to 7q22.1-31.1
We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.
Wang, Min; Li, Xin; Zhang, Feng; Li, Yun; Zhang, Meng; Da, Yuwei; Yu, Jun; Jia, Jianping
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in an Israeli family
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cerebral microangiopathy, and is caused by over 170 different mutations in the NOTCH3 gene at locus 19p13.1–13.26. We report the first study of familial CADASIL in a 39-year-old Jewish woman and her mother who had died previously. The patient's investigations revealed a normal hemogram with no vascular risk factors or chronic disease. Lumbar puncture was normal. Cranial computed tomography scan revealed bilateral diffuse hypodensities in the subcortical white matter. Cranial magnetic resonance imaging showed hyperintense lesions in the cerebral white matter on T2-weighted images. On electron microscopy, a characteristic granular osmiophilic material was seen in the basement membrane surrounding the pericytes and smooth muscle cells in small-sized and medium-sized vessels. Molecular analysis of the NOTCH3 gene was performed with automatic sequencing of exon 3 and 4 (and intron-exon boundaries) showing a nucleotide c.268C > T substitution, leading to a pathogenic amino acid substitution of p.Arg90Cys, confirming a diagnosis of CADASIL. This mutation was also found in the patient's mother. Although the exact prevalence of CADASIL is not known, this disorder has been reported worldwide, and now including Jews, with a genotype and clinical phenotype similar to that in other ethnic groups.
Shahien, Radi; Bianchi, Silvia; Bowirrat, Abdalla
A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1
Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.
Marques-Pinheiro, Alice; Marduel, Marie; Rabes, Jean-Pierre; Devillers, Martine; Villeger, Ludovic; Allard, Delphine; Weissenbach, Jean; Guerin, Maryse; Zair, Yassine; Erlich, Daniele; Junien, Claudine; Munnich, Arnold; Krempf, Michel; Abifadel, Marianne; Jais, Jean-Philippe; Boileau, Catherine; Varret, Mathilde
Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.
A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected. PMID:15221337
Hagel, C; Groden, C; Niemeyer, R; Stavrou, D; Colmant, H J
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in an Israeli family.
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cerebral microangiopathy, and is caused by over 170 different mutations in the NOTCH3 gene at locus 19p13.1-13.26. We report the first study of familial CADASIL in a 39-year-old Jewish woman and her mother who had died previously. The patient's investigations revealed a normal hemogram with no vascular risk factors or chronic disease. Lumbar puncture was normal. Cranial computed tomography scan revealed bilateral diffuse hypodensities in the subcortical white matter. Cranial magnetic resonance imaging showed hyperintense lesions in the cerebral white matter on T2-weighted images. On electron microscopy, a characteristic granular osmiophilic material was seen in the basement membrane surrounding the pericytes and smooth muscle cells in small-sized and medium-sized vessels. Molecular analysis of the NOTCH3 gene was performed with automatic sequencing of exon 3 and 4 (and intron-exon boundaries) showing a nucleotide c.268C > T substitution, leading to a pathogenic amino acid substitution of p.Arg90Cys, confirming a diagnosis of CADASIL. This mutation was also found in the patient's mother. Although the exact prevalence of CADASIL is not known, this disorder has been reported worldwide, and now including Jews, with a genotype and clinical phenotype similar to that in other ethnic groups. PMID:21822390
Shahien, Radi; Bianchi, Silvia; Bowirrat, Abdalla
Genetic linkage of autosomal dominant neovascular inflammatory vitreoretinopathy to chromosome 11q13.
Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an inherited eye disease characterized by retinal and iris neovascularization, abnormal retinal pigmentation, anterior chamber and vitreous inflammation, cystoid macular edema, vitreous hemorrhage, and traction retinal detachment. Some of these clinical features are shared by more common, potentially blinding, conditions including diabetic retinopathy, uveitis, and retinitis pigmentosa. Elucidation of the molecular pathogenesis of ADNIV has the potential to provide insight into the mechanisms of these common disorders. One hundred and sixteen members of an eight generation family affected with ADNIV were examined. A combination of slit lamp biomicroscopy, ophthalmoscopy, and electroretinography was used to establish the diagnosis and 34 family members were found to be affected. Blood samples were obtained from thirty-three of these individuals and nine spouses and used for chromosome linkage analysis with denaturing gradient gel and short tandem repeat polymorphisms. Two markers that map to chromosome 11q13 were found to be significantly linked to the ADNIV phenotype. There were no recombinants between the disease phenotype and marker D11S527 and multipoint analysis yielded a maximum LOD score of 11.9 centered on this marker. PMID:1284594
Stone, E M; Kimura, A E; Folk, J C; Bennett, S R; Nichols, B E; Streb, L M; Sheffield, V C
Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide–dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-?, which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore, treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys, Pkd1 conditional knockout postnatal kidneys, and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD.
Zhou, Xia; Fan, Lucy X.; Sweeney, William E.; Denu, John M.; Avner, Ellis D.; Li, Xiaogang
Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q.
Twenty-one members of a Swedish family suffering from myopathy and cardiomyopathy underwent neurological and cardiological investigations. Medical charts of 2 affected deceased patients were reviewed. Twelve patients had myopathy. The distribution of weakness was axial in mildly affected, axial and predominantly distal in moderately affected, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy revealed granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic right ventribular cardiomyopathy. Nonsustained ventribular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of them had a pacemaker implanted because of atrioventricular block and sick sinus syndrome. Inheritance is autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. Linkage analysis of candidate chromosomal regions showed a maximum 2-point LOD score of 2.76 for marker locus D10S1752 on chromosome 10q. A multipoint peak LOD score of 3.06 between markers D10S605 and D10S215 suggests linkage to chromosome 10q22.3, and this region may harbor a genetic defect for myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopahty. PMID:10970245
Melberg, A; Oldfors, A; Blomström-Lundqvist, C; Stĺlberg, E; Carlsson, B; Larrson, E; Lidell, C; Eeg-Olofsson, K E; Wikström, G; Henriksson, G; Dahl, N
Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by localized autonomous cellular proliferation, fluid accumulation within the cysts, and intraparenchymal fibrosis of the kidney. Little is known about the cyst fluid's protein composition. We hypothesized that the complex collection of cyst fluid proteins (cyst fluid proteome) plays a major role in cyst formation/maintenance and contains yet unknown diagnostic and mechanistic features that are common to all forms of PKD. We analyzed five kidney cyst fluids from four patients with ADPKD. Tryptic peptides from plasma-protein immunodepleted (ProteoPrep®) and undepleted cyst fluid samples were analyzed by LC-MS/MS. Proteins were identified by SEQUEST™ and validated via the Trans-Proteomic Pipeline; 391 proteins were identified with >90% confidence; 251 of them in undepleted and 362 in immunodepleted samples. Immunodepletion removed >94% of the cyst fluid protein. A surprisingly large and functionally diverse number of proteins common to most cysts were identified. These proteins may be of mechanistic interest and include Ig ?, ?, and fragments; complement components; vitronectin; orosomucoid; prostaglandin D2 synthase; vitamin D-binding protein; clusterin; SERPIN family proteins; hemopexin; and fetuin-A. Additionally, these results suggest that further prefractionation and enhanced chromatographic separation of tryptic peptides is likely to expose an even greater number of relevant proteins.
Lai, Xianyin; Bacallao, Robert L.; Blazer-Yost, Bonnie L.; Hong, David; Mason, Stephen B.; Witzmann, Frank A.
Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive hereditary kidney disease. In 85-90% of cases, ADPKD results from a mutation in the PKD1 gene, and the other 10-15% of the cases are accounted for by mutations in PKD2. PKD1 and PKD2 encode polycystin-1 and polycystin-2. Polycystin-1 may be a receptor that controls the channel activity of polycystin-2 as part of the polycystin signaling complex. ADPKD is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that gradually compress the parenchyma and compromise renal function. In recent years, considerable interest has developed in the primary cilia as a site of the proteins that are involved in renal cystogenesis. The pathological processes that facilitate cyst enlargement are hypothesized to result from two specific cellular abnormalities: (1) increased fluid secretion into the cyst lumen and (2) inappropriately increased cell division by the epithelium lining the cyst. Since there is no clinically approved specific or targeted therapy, current practice focuses on blood pressure control and statin therapy to reduce the cardiac mortality associated with chronic kidney disease. However, recent advances in our understanding of the pathways that govern renal cystogenesis have led to a number of intriguing possibilities in regard to therapeutic interventions. The purpose of this article is to review the pathogenesis of renal cyst formation and to review novel targets for the treatment of ADPKD. PMID:23192769
Mochizuki, Toshio; Tsuchiya, Ken; Nitta, Kosaku
Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease.
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-?, which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore, treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys, Pkd1 conditional knockout postnatal kidneys, and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD. PMID:23778143
Zhou, Xia; Fan, Lucy X; Sweeney, William E; Denu, John M; Avner, Ellis D; Li, Xiaogang
[Analysis of mutations in patients with suspected autosomal dominant form of the Parkinson disease].
The Parkinson disease (PD) is a severe neurological disorder. Diverse genetic systems and environmental factors are involved in the pathogenesis of this disease. However, despite extensive research into the disease, its causes are not fully elucidated, and the exact spectrum of genes and mutations involved in the development of hereditary forms of PD has not been fully clarified yet. The present work is devoted to the analysis of mutations that lead to the development of monogenic forms of PD in patients with suspected autosomal dominant form of PD using Multiplex Ligation-dependent Probe Amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2-3, 3-4 exons and heterozygous duplication of 2-4 exons in PARK2, deletion of 3 exon in PARK7) that lead to the development of PD in only 7 people out of 70 (18.4%), which suggests the need for further search of new mutations, for example, using exome sequencing. In the future it will help to develop the molecular genetic tests for early preclinical diagnosis and risk evaluation of the development of PD, and to understand better the causes and mechanisms of this disease. PMID:24757835
Genotyping microarray: Mutation screening in Spanish families with autosomal dominant retinitis pigmentosa
Purpose Presently, 22 genes have been described in association with autosomal dominant retinitis pigmentosa (adRP); however, they explain only 50% of all cases, making genetic diagnosis of this disease difficult and costly. The aim of this study was to evaluate a specific genotyping microarray for its application to the molecular diagnosis of adRP in Spanish patients. Methods We analyzed 139 unrelated Spanish families with adRP. Samples were studied by using a genotyping microarray (adRP). All mutations found were further confirmed with automatic sequencing. Rhodopsin (RHO) sequencing was performed in all negative samples for the genotyping microarray. Results The adRP genotyping microarray detected the mutation associated with the disease in 20 of the 139 families with adRP. As in other populations, RHO was found to be the most frequently mutated gene in these families (7.9% of the microarray genotyped families). The rate of false positives (microarray results not confirmed with sequencing) and false negatives (mutations in RHO detected with sequencing but not with the genotyping microarray) were established, and high levels of analytical sensitivity (95%) and specificity (100%) were found. Diagnostic accuracy was 15.1%. Conclusions The adRP genotyping microarray is a quick, cost-efficient first step in the molecular diagnosis of Spanish patients with adRP.
Garcia-Hoyos, Maria; Corton, Marta; Avila-Fernandez, Almudena; Riveiro-Alvarez, Rosa; Gimenez, Ascension; Hernan, Inma; Carballo, Miguel; Ayuso, Carmen
A family of autosomal dominant hypocalcemia with an activating mutation of calcium-sensing receptor gene.
Autosomal dominant hypocalcemia (ADH) caused by activating mutations of calcium-sensing receptor (CaSR) is characterized by hypocalcemia with inappropriately low concentration of PTH and relative hypercalciuria. Active vitamin D treatment often leads to nephrolithiasis and renal impairment in patients with ADH. However, differential diagnosis between ADH and idiopathic hypoparathyroidism is sometimes very difficult. Here, we report a mutation of CaSR and its functional property found in three generations of a Japanese family. The proband developed seizures at 7 days of age. His mother and elder sister were discovered to have hypoparathyroidism by family survey, but his father was normocalcemic. His grandfather developed heart failure and was found to have hypoparathyroidism. All affected members had been treated with active vitamin D3 and bilateral nephrolithiasis were detected in three of them. DNA sequencing revealed that all affected patients had a heterozygous mutation in CaSR gene that causes proline to leucine substitution at codon 221 (P221L). In vitro functional analysis of the mutant CaSR by measuring inositol 1,4,5-trisphosphate production in response to changes of extracellular Ca indicated that this mutation is an activating one and responsible for ADH in this family. Therefore, careful monitoring of urinary Ca excretion before and during treatment of PTH-deficient hypoparathyroidism is very important, and screening of CaSR mutation should be considered in patients with relative hypercalciuria or with a family history of hypocalcemia. PMID:12733714
Chikatsu, Noriko; Watanabe, Sumiyo; Takeuchi, Yasuhiro; Muraosa, Yasushi; Sasaki, Shinsuke; Oka, Yuji; Fukumoto, Seiji; Fujita, Toshiro
An autosomal dominant cataract locus mapped to 19q13-qter in a Chinese family
Purpose The aim of this study was to map the disease locus of autosomal dominant cataracts (ADC) in a Chinese family. Methods A four-generation family with multiple individuals affected by ADC was investigated. Genomic DNA was collected from 22 family members. A gene-scan at known candidate ADC loci was performed. To achieve fine-mapping we genotyped fourteen STR markers at the critical region of 19q. The two-point logarithm of odds (LOD) score was calculated using Linkage Software Package Version 5.1 for linkage analysis. The haplotype was constructed using Cyrillic software. Results Ten members of this Chinese family were affected by nuclear cataracts. Initially, linkage analysis revealed a significant LOD score of 3.82 at the STR marker D19S418. Subsequently, after refine-marker analysis, a maximum LOD score (Zmax=4.25) was obtained at the D19S877 (?=0). Haplotype analysis also confirmed the locus and further narrowed it down to a critical interval from the marker D19S924 to the 19qter. Conclusions We have successfully mapped an ADC locus to 19q13-qter. Previous studies have identified three cataract loci on 19q; however, we found no overlap between the locus of this study and any of the previously identified loci. We therefore suggest that the 19q13-qter locus in this family is a new locus for ADC.
Zhao, Rui; Yang, Yonjia; He, Xinyu; Liu, Zheng; Wang, Pin; Zhou, Lijun; Tang, Jinsong; Xu, Wei; Li, Liping
Singleton-Merten syndrome: an autosomal dominant disorder with variable expression.
In 1973, Singleton and Merten described two females with abnormal dentition, unique radiographic changes especially of the hands, and severe calcification and intimal weakening of the aortic arch and valve. Since then three additional cases with similar features have been reported and the diagnosis was suggested in another three individuals. We present an update of one case and the detailed clinical phenotype of six other cases with Singleton-Merten syndrome. The occurrence of the disorder in six members of two families and vertical male-to-male transmission indicate an autosomal dominant pattern of inheritance. Variability in phenotype, also within a single family, is significant. Core manifestations are marked aortic calcification, dental anomalies (delayed eruption and immature root formation of primarily the anterior permanent teeth, and early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss), osteopenia and acro-osteolysis, and to a lesser extend also glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical characteristics described here include particular facial characteristics (high anterior hairline, broad forehead, smooth philtrum, thin upper vermillion) and abnormal joint and muscle ligaments. The cause and pathogenesis of this syndrome remain unknown. © 2013 Wiley Periodicals, Inc. PMID:23322711
Feigenbaum, Annette; Müller, Christine; Yale, Christopher; Kleinheinz, Johannes; Jezewski, Peter; Kehl, Hans Gerd; MacDougall, Mary; Rutsch, Frank; Hennekam, Raoul C M
Pathogenesis of Autosomal Dominant Hereditary Spastic Paraplegia (SPG6) Revealed by a Rat Model
Abstract Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1G106R) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1G106R mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1G106R Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms.
Watanabe, Fumihiro; Arnold, William D.; Hammer, Robert E.; Ghodsizadeh, Odelia; Moti, Harmeet; Schumer, Mackenzie; Hashmi, Ahmed; Hernandez, Anthony; Sneh, Amita; Sahenk, Zarife
[Autosomal dominant spinocerebellar degeneration with pigmentary retinopathy in a Japanese family].
We report a pedigree of autosomal dominant spinocerebellar degeneration associated with pigmental retinopathy. The proband is a 75-year-old man. He noticed night blindness at the age of 10 years and a diagnosis of bilateral pigmentary retinopathy was made at age 63. At the age of 65 years, he developed dysarthria and difficulty in walking. At age 69, neurological examination revealed cerebellar signs, and brain CT scans showed mild atrophy of the brain stem and cerebellum. Repeated brain CT scans revealed slight progression of the brain stem and cerebellar atrophy. Molecular genetic studies showed the absence of any mitochondrial DNA mutation at 8993. The father of the proband exhibited cerebellar signs and pigmentary retinopathy. One older brother had cerebellar signs and another had pigmentary retinopathy. To our knowledge, hereditary spinocerebellar degeneration with retinal degeneration is rare in Japan. This study is the first full report on hereditary spinocerebellar degeneration with pigmentary retinopathy in Japan, although an abstract was published by Konishi et al. We also discuss the neuropathological discordance on hereditary olivoponto-cerebellar atrophy with retinal degeneration. PMID:7873282
Tsuchiya, K; Watabiki, S; Owada, K; Uchihara, T; Yamamoto, M; Hamada, K; Misawa, A; Taki, K
Mutation of the PAX6 gene in patients with autosomal dominant keratitis.
Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; theta = .00 with D11S914), consistent with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The SeyNeu mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the SeyNeu mouse is an excellent animal model of ADK. The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations. Images Figure 2 Figure 1 Figure 3
Mirzayans, F; Pearce, W G; MacDonald, I M; Walter, M A
Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.
Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterised by pyramidal, cerebellar, and autonomic disturbances. Duplication of the LMNB1 gene is the genetic cause of ADLD, yet the pathogenetic mechanism is not defined. In this study, we analysed cells and muscle tissue from three patients affected by ADLD, carrying an extra copy of the LMNB1 gene. Lamin B1 levels were dramatically increased in ADLD nuclei, both in skin fibroblasts and skeletal muscle fibres. Since lamin B1 is known to bind Oct-1, a transcription factor involved in the oxidative stress pathway, we investigated Oct-1 fate in ADLD. Oct-1 recruitment to the nuclear periphery was increased in ADLD cells, while nucleoplasmic localisation of the transcription factor under oxidative stress conditions was reduced. Importantly, lamin B1 degradation occurring in some, but not all ADLD cell lines, slowed down lamin B1 and Oct-1 accumulation. In skeletal muscle, focal disorganisation of sarcomeres was observed, while IIB-myosin heavy chain, an Oct-1 target gene, was under-expressed and rod-containing fibres were formed. These data show that a high degree of regulation of lamin B1 expression is implicated in the different clinical phenotypes observed in ADLD and show that altered Oct-1 nuclear localisation contributes to the disease phenotype. PMID:23261988
Columbaro, Marta; Mattioli, Elisabetta; Maraldi, Nadir M; Ortolani, Michela; Gasparini, Laura; D'Apice, Maria Rosaria; Postorivo, Diana; Nardone, Anna Maria; Avnet, Sofia; Cortelli, Pietro; Liguori, Rocco; Lattanzi, Giovanna
Poikiloderma, tendon contracture and pulmonary fibrosis: a new autosomal dominant syndrome?
Members of two generations of a South African family have a unique syndrome comprising poikiloderma, tendon contractures and progressive pulmonary fibrosis. The condition is clinically important as the skin changes, which involve the face, have considerable cosmetic impact, while lung involvement is potentially lethal in adulthood. Skin manifestations which facilitate diagnosis include facial telangiectasia, mottled hypo- and hyperpigmentation, papules and epidermal atrophy. The scalp, facial and body hair are fine and scanty. The tendon contractures lead to progressive digital flexion deformities and abnormalities of the ankles and feet, with disturbance of gait. Pulmonary involvement manifests as progressive dyspnoea. Pedigree data are compatible with an autosomal dominant mode of transmission. Poikiloderma of Weary is characterized by linear sclerotic and fibrous bands and not tendon contractures and is not associated with potentially lethal pulmonary fibrosis. Rather than name this disorder a variant of Weary syndrome, it might be prudent to use as an umbrella title one composed by Weary himself: 'hereditary sclerosing poikiloderma' (HSP), under which variants such as HSP Weary type, HSP with cardiac involvement (aortic stenosis described as inconsistently associated with Weary syndrome) and HSP with tendon/pulmonary involvement (current family) may be classified. The manifestations in this family differ from other poikilodermata and, to the best of our knowledge, have not been previously documented. PMID:17034542
Khumalo, N P; Pillay, K; Beighton, P; Wainwright, H; Walker, B; Saxe, N; Mayosi, B M; Bateman, E D
The gene expression profile of cyst epithelial cells in autosomal dominant polycystic kidney disease patients.
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the formation of fluid-filled cysts in the kidney and progressive renal failure. Other manifestations of ADPKD include the formation of cysts in other organs (liver, pancreas, and spleen), hypertension, cardiac defects, and cerebral aneurysms. The loss of function of the polycystin -1 and -2 results in the formation of epithelium-lined cysts, a process that depends on initial epithelial proliferation. cDNA microarrays powerfully monitor gene expression and have led to the discoveries of pathways regulating complex biological processes. We undertook to profile the gene expression patterns of epithelial cells derived from the cysts of ADPKD patients using the cDNA microarray technique. Candidate genes that were differently expressed in cyst tissues were identified. 19 genes were up-regulated, and 6 down-regulated. Semi-quantitative RT-PCR results were consistent with the microarray findings. To distinguish between normal and epithelial cells, we used the hierarchical method. The results obtained may provide a molecular basis for understanding the biological meaning of cytogenesis. PMID:15479626
Lee, Jae Eun; Park, Min Ha; Park, Jong Hoon
A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy
Highlights: Black-Right-Pointing-Pointer We report the characterization of a four-generation large Chinese family with ADOA. Black-Right-Pointing-Pointer We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. Black-Right-Pointing-Pointer We do not find any mitochondrial DNA mutations associated with optic atrophy. Black-Right-Pointing-Pointer Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.
Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Dai, Xianning; Zhou, Huihui [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China)] [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Dong, Xujie [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Liu, Xiao-Ling, E-mail: email@example.com [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Guan, Min-Xin, E-mail: email@example.com [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China) [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang 310012 (China); Division of Human Genetics, Cincinnati Children's Hospital Medical Center, OH 45229 (United States)
A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.
Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk.
Coon, H; Jensen, S; Hoff, M; Holik, J; Plaetke, R; Reimherr, F; Wender, P; Leppert, M; Byerley, W
Nephrotic syndrome and idiopathic membranous nephropathy associated with autosomal-dominant polycystic kidney disease.
We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD) and concomitant nephrotic syndrome secondary to membranous nephropathy (MN). A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM) 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function. PMID:21552769
Peces, Ramón; Martínez-Ara, Jorge; Peces, Carlos; Picazo, Mariluz; Cuesta-López, Emilio; Vega, Cristina; Azorín, Sebastián; Selgas, Rafael
Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa
Purpose Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. Methods We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. Results We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5? untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. Conclusions The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.
Benaglio, Paola; San Jose, Patricia Fernandez; Avila-Fernandez, Almudena; Ascari, Giulia; Harper, Shyana; Manes, Gael; Ayuso, Carmen; Hamel, Christian; Berson, Eliot L.
Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele
Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. ADPKD is a systemic disorder with cysts and connective tissue abnormalities involving many organs. ADPKD caused by mutations in PKD1 gene is significantly more severe than the cases caused by PKD2 gene mutations. The large intra-familial variability of ADPKD highlights a role for genetic background. Case presentation Here we report a case of ADPKD family initially appearing unlinked to the PKD1 or PKD2 loci and the influence of mosaicism and hypomorphic allele on the variability of the clinical course of the disease. A grandmother with the PKD1 gene mutation in mosaicism (p.Val1105ArgfsX4) and with mild clinical course of ADPKD (end stage renal failure at the age of 77) seemed to have ADPKD because of PKD2 gene mutation. On the other hand, her grandson had a severe clinical course (end stage renal disease at the age of 45) in spite of the early treatment of mild hypertension. There was found by mutational analysis of PKD genes that the severe clinical course was caused by PKD1 gene frameshifting mutation inherited from his father and mildly affected grandmother in combination with inherited hypomorphic PKD1 allele with described missense mutation (p.Thr2250Met) from his clinically healthy mother. The sister with two cysts and with PKD1 hypomorphic allele became the kidney donor to her severely affected brother. Conclusion We present the first case of ADPKD with the influence of mosaicism and hypomorphic allele of the PKD1 gene on clinical course of ADPKD in one family. Moreover, this report illustrates the role of molecular genetic testing in assessing young related kidney donors for patients with ADPKD.
Allele-Specific Gene Silencing in Two Mouse Models of Autosomal Dominant Skeletal Myopathy
We explored the potential of mutant allele-specific gene silencing (ASGS) in providing therapeutic benefit in two established mouse models of the autosomal dominantly-inherited muscle disorders, Malignant Hyperthermia (MH) and Central Core Disease (CCD). Candidate ASGS siRNAs were designed and validated for efficacy and specificity on ryanodine receptor (RyR1) cDNA mini-constructs expressed in HEK293 cells using RT-PCR- and confocal microscopy-based assays. In vivo delivery of the most efficacious identified siRNAs into flexor digitorum brevis (FDB) muscles was achieved by injection/electroporation of footpads of 4–6 month old heterozygous Ryr1Y524S/+ (YS/+) and Ryr1I4895T/+ (IT/+) knock-in mice, established mouse models of MH with cores and CCD, respectively. Treatment of IT/+ mice resulted in a modest rescue of deficits in the maximum rate (?38% rescue) and magnitude (?78%) of ligand-induced Ca2+ release that occurred in the absence of a change in the magnitude of electrically-evoked Ca2+ release. Compared to the difference between the caffeine sensitivity of Ca2+ release in FDB fibers from YS/+ and WT mice treated with SCR siRNA (EC50: 1.1 mM versus 4.4 mM, respectively), caffeine sensitivity was normalized in FDB fibers from YS/+ mice following 2 (EC50: 2.8 mM) and 4 week (EC50: 6.6 mM) treatment with YS allele-specific siRNA. Moreover, the temperature-dependent increase in resting Ca2+ observed in FDB fibers from YS/+ mice was normalized to WT levels after 2 weeks of treatment with YS allele-specific siRNA. As determined by quantitative real time PCR, the degree of functional rescue in YS/+ and IT/+ mice correlated well with the relative increase in fractional WT allele expression.
Loy, Ryan E.; Lueck, John D.; Mostajo-Radji, Mohammed A.; Carrell, Ellie M.; Dirksen, Robert T.
Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis
Objective Pseudohypoparathyroidism (PHP) is a heterogeneous disorder characterized by hypocalcemia and hyperphosphatemia resulting from selective renal resistance to parathyroid hormone (PTH). One autosomal dominant form of PHP type 1b (PHP-Ib) is most frequently caused by a maternally inherited 3-kb deletion within STX16, the gene encoding syntaxin 16. To date, increased bone mineral density (BMD) has been described only in PHP type 1a, and there is a lack of detailed information on bone histomorphometry in PHP-Ib. The objective of this report was to present trans-iliac static and dynamic histomorphometry in two brothers with the 3-kb deletion in the STX16 region and elevated BMD. Design Observational study of two brothers (age 18.0 and 22.7 years) with the 3-kb STX16 deletion and increased BMD. Results The brothers had elevated PTH (146 pg/ml (15.6 pmol/l) and 102 pg/ml (10.9 pmol/l); normal: 10–64 pg/ml (1.1–6.8 pmol/l)) and striking osteosclerosis (lumbar spine areal BMD Z-scores: +5.4 and +4.9). Bone histomorphometry showed marked elevations in cortical width for both brothers (241 and 209% of the mean result expected for age), with elevations in the bone formation rate on the endocortical (119 and 260% of the healthy mean) and trabecular (220 and 190% of mean) surfaces. Conclusion Our findings suggest that PTH in this PHP-Ib genotype can increase cortical thickness due to its anabolic effect on endocortical bone, and underscore the heterogeneity in the skeletal phenotype among patients with PHP-Ib.
Sbrocchi, Anne Marie; Rauch, Frank; Lawson, Margaret L; Hadjiyannakis, Stasia; Lawrence, Sarah; Bastepe, Murat; Juppner, Harald; Ward, Leanne Marie
Fluocinolone Acetonide Implant Inhibits Neovascularization but not Fibrosis in Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy
Objective To review the effect of the fluocinolone acetonide implant (FA) in subjects with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV), an inherited, autoimmune uveitis. Methods A retrospective case series was assembled from ADNIV patients who underwent fluocinolone acetonide implantation. Visual acuity and features of ADNIV, including inflammatory cells, neovascularization, fibrosis, and cystoid macular edema were reviewed. Results Nine eyes of five related ADNIV patients with uncontrolled inflammation were reviewed. Follow-up ranged 21.7–56.7 months. Vision at implantation ranged from 20/40 to hand motion. Preoperatively, eight eyes demonstrated vitreous cell (an eighth had a diffuse vitreous hemorrhage). Eight eyes demonstrated cystoid macular edema, seven had an epiretinal membrane, and three manifested retinal neovascularization. Following implantation, vitreous cells resolved in all eyes and neovascularization regressed or failed to develop. Central macular thickness improved in four eyes. During the postoperative course, however, visual acuity continued to deteriorate, with vision at the most recent examination ranging from 20/60 to no light perception. There was also progressive intraocular fibrosis and phthisis in one case. Four eyes underwent cataract surgery. Six of the seven eyes without previous glaucoma surgery demonstrated elevated intraocular pressure at some point, and three of these required glaucoma surgery. Conclusions FA implantation may inhibit specific features of ADNIV such as inflammatory cells and neovascularization, but does not stabilize long-term vision, retinal thickening, or fibrosis. All eyes in this series required cataract extraction, and more than half required surgical intervention for glaucoma. Further studies may identify additional therapies and any benefit of earlier implantation.
Tlucek, Paul S.; Folk, James C.; Orien, Jason A.; Stone, Edwin M.; Mahajan, Vinit B.
Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia.
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity. HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending (pyramidal) and ascending (dorsal columns) tracts. In this study, we compared spinal cord magnetic resonance imaging (MRI) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia (SPG3A, SPG4, SPG6, and SPG8) with age-matched control subjects. The cross-section area of HSP subjects at cervical level C2 was 59.42 +/- 12.57 mm2 and at thoracic level T9 was 28.58 +/- 5.25 mm2. Both of these values were less than in the healthy controls (p < 0.001). The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy (47.60 +/- 6.58 mm2 at C2, 21.40 +/- 2.4 mm2 at T9) than in subjects with SPG3 and SPG4 (66.0 +/- 8.94 mm2 at C2, p < 0.02; 31.75 +/- 2.76 mm2 at T9, p < 0.001). These observations indicate that spinal cord atrophy is a common finding in the four genetic types of HSP. Spinal cord atrophy was more severe in SPG6 and SPG8 HSP subjects than in other types of HSP we studied. This may suggest a different disease mechanism with more prominent axonal degeneration in these two types of HSP when compared with HSP due to spastin and atlastin mutations. PMID:16143870
Hedera, P; Eldevik, O P; Maly, P; Rainier, S; Fink, J K
Mutation G61C in the CRYGD gene causing autosomal dominant congenital coralliform cataracts
Purpose We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital coralliform cataracts and demonstrate the functional analysis of a candidate gene in the family. Methods Family history data were recorded. Clinical and ophthalmologic examinations were performed on affected and unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated using the Linkage software after genotyping. A mutation was detected by direct sequencing, using gene-specific primers. Wild-type and mutant proteins were analyzed with online software. Results Affected members of this family had coralliform cataracts. Linkage analysis was obtained at markers, D2S72 (LOD score [Z]=3.31, recombination fraction [?]=0.0) and D2S1782 (Z=3.01, ?=0.0). Haplotype analysis indicated that the cataract gene was closely linked to these two markers. Sequencing the ?D-crystallin gene (CRYGD) revealed a G>T transversion in exon 2, which caused a conservative substitution of Gly to Cys at codon 61 (P.G61C). This mutation co-segregated with the disease phenotype in all affected individuals and was not observed in any of the unaffected or 100 normal, unrelated individuals. Bioinformatic analyses showed that a highly conserved region was located around Gly61. Data generated with online software revealed that the mutation altered the protein's stability, solvent-accessibility, and interactions with other proteins. Conclusions This is the first reported case of a congenital coralliform cataract phenotype associated with the mutation of Gly61Cys (P.G61C) in the CRYGD gene; it demonstrates a possible mechanism of action for the mutant gene.
Li, Feifeng; Wang, Shuzhen; Gao, Chang; Liu, Shiguo; Zhao, Baojian; Zhang, Meng; Huang, Shangzhi; Zhu, Siquan
Berberine slows cell growth in autosomal dominant polycystic kidney disease cells.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 ?g/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 ?g/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G0/G1 phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities for the therapy of ADPKD patients. PMID:24184483
Bonon, Anna; Mangolini, Alessandra; Pinton, Paolo; Del Senno, Laura; Aguiari, Gianluca
Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous disease caused by mutations in PKD1 and PKD2. The genotype-phenotype correlations are not completely understood. We performed direct PCR-sequencing plus multiplex ligation-dependent probe amplification for PKD1 and PKD2 in 46 unrelated patients. Disease-causing mutations were identified in 30 (65%) patients: 23 (77%) patients have mutations in PKD1 and 7 (23%) have mutations in PKD2. Nonsense, splicing or frame-shifting mutations were found in 18 patients, exon duplication in 1 and missense mutations in 11 patients. Two likely PKD1 hypomorphic alleles (p.Arg2477His and p.Arg3439Trp) segregated with mild disease in a family. A total of 34 mutations were identified and 17 (50%) of which are novel. The median age at onset of dialysis was significantly earlier in patients with PKD1 mutations (52 years) than in patients with PKD2 mutations (65.5 years) and those with an undetermined genotype (67 years) by survival analysis (log-rank test, P=0.014). Patients carrying PKD1-truncating mutations have a trend toward earlier initiation of dialysis compared with carriers of non-truncating mutations (52 years vs 57 years, P=0.061). A family history of dialysis before 55 years was more common in PKD1 patients than in others (P<0.05). In conclusion, this study identified novel mutations in PKD1 and PKD2 and demonstrated the presence of PKD1 hypomorphic alleles in Taiwanese patients. Patients carrying PKD1 mutations, especially those with truncating mutations, could have a more rapidly progressive disease than others. These results might have implications for diagnosis and risk stratification in patients with ADPKD. PMID:23985799
Chang, Ming-Yang; Chen, Hsiao-Mang; Jenq, Chang-Chyi; Lee, Shen-Yang; Chen, Yu-Ming; Tian, Ya-Chung; Chen, Yung-Chang; Hung, Cheng-Chieh; Fang, Ji-Tseng; Yang, Chih-Wei; Wu-Chou, Yah-Huei
Management of nephrolithiasis in autosomal dominant polycystic kidney disease -- A single center experience
Purpose: To evaluate available options for the management of nephrolithiasis in patients with autosomal dominant polycystic kidney disease (ADPKD). Materials and Methods: Case files of all the patients with ADPKD treated in our hospital in the last 18 years were evaluated. Their demographic details, clinical presentations, investigations, treatments, and outcomes were critically analyzed. Results: There were a total of 19 patients (23 renal units) with nephrolithiasis among 452 consecutive cases of ADPKD. Male-to-female ratio was 3.75:1. The mean age of the patients was 43.3 years (range 23 to 60 years). The most common presentations were pain and hematuria (27.7% each). Mean serum creatinine was 7.2 mg/ dl (range 0.8-18.1 mg/dl) at presentation. The mean stone size was 115 mm2 (range 36 to 980 mm2). The majority of the stones were calyceal (n = 10). Ten renal units (nine patients) required intervention, while the rest were treated conservatively. Treatment offered included open nephrectomy for non-functioning infected kidney (n = 1), extracorporeal shock wave lithotripsy (ESWL, n = 3), ureterorenoscopy (URS, n = 3), and percutaneous nephrolithotomy (PCNL, n = 3). All patients undergoing URS and PCNL had complete clearance, while those undergoing ESWL had a residual stone. Two failed ESWL patients required an auxiliary procedure (retrograde intrarenal surgery, RIRS) and the other was kept under observation. Mean follow-up after treatment was 4.2 years (one month to six years). None of the patients had major complications. Conclusion: Careful selection of the endourological procedure can give good results in patients of ADPKD with nephrolithiasis.
Baishya, Ramen; Dhawan, Divya R.; Kurien, Abraham; Ganpule, Arvind; Sabnis, Ravindra B.; Desai, Mahesh R.
Hyperbaric oxygen therapy in a patient with autosomal dominant polycystic kidney disease with a perinephritic abscess.
A 68-year-old female in hemodialysis due to autosomal dominant polycystic kidney disease underwent resection of cysts in her right kidney via a laparoscopic approach due to abdominal pain. Three weeks after surgery, she was admitted with sepsis. A CT scan showed a large abscess around the right kidney. Percutaneous drainage of abscess was performed. The pus smear showed Gram-positive cocci and the culture contained methicillin-resistant Staphylococcus aureus. Ciprofloxacin, clindamycin and vancomycin were given. In the 3 weeks following admission, she remained febrile and septic and showed a progressive deterioration in her general condition, along with malnutrition and persistent drainage of purulent material from her right flank. The antibiotic therapy was changed to vancomycin, metronidazole and meropenem, but no improvement was observed. Because of the high risk associated with carrying out an open nephrectomy, we decided to use hyperbaric oxygen therapy (HBOT) as a potentially useful measure to control her infection. The patient underwent 26 daily sessions of 100% hyperbaric oxygen (2.5 atm). The use of HBOT induced a notable break in the clinical course of this patient's retroperitoneal infection. She was discharged after day 58 without any signs of inflammatory activity, and she has not presented reactivation of infection since then. We think that this case suggests that this therapy could be a new therapeutic tool in the management of patients with similar clinical features when all other therapeutic measures have failed. We did not find any other reports of the use of HBOT in infections of renal cysts. PMID:20886361
Vega, Jorge; Goecke, Helmuth; Manriquez, Francisco; Escobar, Carlos; Escobar, Max; Videla, Christian; Santamarina, Mario; Echeverria, Carlos; Guarda, Francisco Javier
Gene localization for an autosomal dominant familial periodic fever to 12p13.
We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.
Mulley, J; Saar, K; Hewitt, G; Ruschendorf, F; Phillips, H; Colley, A; Sillence, D; Reis, A; Wilson, M
The Genetics of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
The most important extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD) in terms of debilitating injury and premature death is the development of intracranial aneurysms (IAs) and other vascular complications, resulting in subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these proteins leads to IA development in mouse models, suggests a direct role of these proteins in the vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5' half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without ADPKD have identified a number of genes/proteins that may be risk factors for the development of IAs. These candidate proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions.
Rossetti, Sandro; Harris, Peter C.
Novel PRPF31 mutations associated with Chinese autosomal dominant retinitis pigmentosa patients
Purpose To identify the mutations in the pre-mRNA processing factor 31 homolog (PRPF31) gene in Chinese families with autosomal dominant retinitis pigmentosa (adRP) and to characterize the clinical features of those patients who were found to have mutations in the PRPF31 gene. Methods Detailed ocular examinations were performed, and genomic DNA was isolated by standard methods for genetic diagnosis. Probands from each family were screened for mutations in the PRPF31 gene that was known to cause adRP. Cosegregation analysis was performed in the available family members. Linkage analysis was performed for one missense mutation to calculate the likelihood of its pathogenicity. Two hundred unrelated, healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms. Results Forty Chinese families with adRP were selected by an analysis of pedigrees. We identified four mutations (c.196_197delAA, c.544_618del75bp, c.615delC, and c.895T>C) in total, and three deletions were novel. Cosegregation analysis of the available family members (20 patients and 17 unaffected family members) revealed that each index patient and all affected family members showed a heterozygous mutation in the PRPF31 gene. In two families, incomplete penetrance was observed. Linkage analysis achieved the maximum LOD score of c.895T>C is 2.09, achieved at ?=0. The four probands with PRPF31 mutations showed classical signs of RP, with relatively preserved central vision and severe visual field constriction. Conclusions Our studies extended the mutation spectrum of PRPF31, and mutations in PRPF31 were found at a relatively high frequency (10%, 4 of 40 adRP families) in our cohort.
Xu, Fei; Sui, Ruifang; Liang, Xiaofang; Li, Hui; Jiang, Ruxin
Berberine slows cell growth in autosomal dominant polycystic kidney disease cells
Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 ?g/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 ?g/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities for the therapy of ADPKD patients.
Bonon, Anna; Mangolini, Alessandra [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Pinton, Paolo [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy)] [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy); Senno, Laura del [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Aguiari, Gianluca, E-mail: firstname.lastname@example.com [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)
A novel prophylactic effect of furosemide treatment on autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
The transgenic rat strain S284L-TG harbors the S284L mutant of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4), which is responsible for human autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). S284L-TG rats have epileptic seizure phenotypes during slow-wave sleep, similar to those in NFLE. We previously demonstrated that ?-aminobutyric acid (GABA)ergic action of these rats was suppressed before the onset of ADNFLE seizures, and that glutamate release in the epileptic focus lesion was increased at the onset of epilepsy. Here, mRNA analysis revealed that Cl(-)-accumulating Na-K-2Cl cotransporter 1 (NKCC1) levels were increased and Cl(-)-extruding K-Cl cotransporter 1 and 2 (KCC1 and KCC2) levels were decreased at the onset of ADNFLE seizures in S284L-TG rat frontal cortexes, which perturbed the GABAergic inhibitory system. The reversal potentials (EGABA) of GABAA receptor-mediated currents in cortical layer V pyramidal neurons of S284L-TG rats also changed their polarity from hyperpolarization to depolarization, and S284L-TG miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs), significantly increased in both amplitude and frequency. Administration of 25mg/kg/day furosemide before, but not after, the onset of interictal discharges prevented idiopathic epileptic activity, reversed the depolarizing shift of EGABA and increased mEPSC amplitude to normal levels. These data indicate that early treatment with an agent that normalizes pathogenesis has a prophylactic effect on epilepsy. We propose a strategy for prophylactic medication against idiopathic epilepsy through the suppression of epileptogenesis and/or ictogenesis. PMID:24045013
Yamada, Junko; Zhu, Gang; Okada, Motohiro; Hirose, Shinichi; Yoshida, Shukuko; Shiba, Yuko; Migita, Keisuke; Mori, Fumiaki; Sugawara, Takayuki; Chen, Lei; Liu, Fang; Yoshida, Shuichi; Ueno, Shinya; Kaneko, Sunao
Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease
Background The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline. Methods This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR)???15 mL/min/1.73 m2 and who were followed up for?>?1 year were included in our analysis. Hyperuricemia was defined by a sUA level of???7.0 mg/dL in male and???6.0 mg/dL in female or when hypouricemic medications were prescribed. Results Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (?6.3% per year vs. ?0.9% per year, p?=?0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: ?5.3?±?8. 2 vs. 0.2?±?6.2 mL/min/1.73 m2 per year, p?=?0.001 by Wilcoxon signed-rank test). Conclusions Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.
Very High Prevalence of Right-to-Left Shunt on Transcranial Doppler in an Italian Family with Cerebral Autosomal Dominant Angiopathy with Subcortical Infarcts and Leukoencephalopathy
Background and Purpose: Cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant hereditary disease whose clinical expression is a stepwise subcortical vascular dementia. Initial presentation of the disease involves transient or stabilized focal neurological deficits, migraine and mood changes. Recently, a high prevalence of right-to-left shunt (RLS) due to patent foramen ovale has been reported
Silvia Angeli; Paola Carrera; Massimo Del Sette; Andrea Assini; Marina Grandis; Donatella Biancolini; Maurizio Ferrari; Carlo Gandolfo
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a clinicopathological and genetic study of a Swiss family
This paper reports a Swiss family affected by a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) linked to chromosome 19q12. In three generations several members of this family had recurrent stroke-like episodes and, some developed subcortical dementia, migraine-like headaches, and depression. The clinically affected family members had multiple subcortical infarcts and diffuse leukoencephalopathy on MRI. Necropsy of
H H Jung; C Bassetti; E Tournier-Lasserve; K Vahedi; M Arnaboldi; V B Arifi; J M Burgunder
Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile\\u000a dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal.\\u000a The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter\\u000a changes in the brain and spinal cord on magnetic resonance imaging
Jens Schuster; Jimmy Sundblom; Ann-Charlotte Thuresson; Sharon Hassin-Baer; Thomas Klopstock; Martin Dichgans; Oren S. Cohen; Raili Raininko; Atle Melberg; Niklas Dahl
Autosomal dominant peripheral cystic retinal patches and non-cystic retinal tufts associated with peripapillary crescents, retinal breaks and uveitis
Purpose: To characterise an Irish kindred with apparent autosomal dominant peripheral retinal lesions and peripapillary crescents associated with retinal breaks and uveitis and assess whether these findings were associated with altered homocysteine metabolism. Methods: Family members were followed prospectively and regularly examined. Molecular genetic analysis was performed on family members to detect cystathionine #-synthase (CBS) 307G-S and 5,10-methylenetetrahydrofolate (MTHFR) 677C-T
Mark Cahill; Paula Gallagher; Alexander Whitehead; Robert Acheson
Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4
The aim of our study was to evaluate Motor Evoked Potentials (MEPs) and cortical excitability, using Transcranial Magnetic Stimulation (TMS) as well as short latency Somatosensory Evoked Potentials (SEPs) in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) patients.MEPs were recorded from upper and lower limb muscles in 12 patients (7m and 5f) affected by ADHSP with spastin mutation (SPG4). We measured:
F. Sartucci; S. Tovani; L. Murri; L. Sagliocco
Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p21–p22 has been shown to account for 40–50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval,
Nůria Fonknechten; Delphine Mavel; Caroline Paternotte; Delphine Samson; François Artiguenave; Claire-Sophie Davoine; Corinne Cruaud; Alexandra Dürr; Patrick Wincker; Philippe Brottier; Laurence Cattolico; Valérie Barbe; Jean-Marc Burgunder; Jean-François Prud'homme; Alexis Brice; Bertrand Fontaine; Roland Heilig; Jean Weissenbach; Jamilé Hazan
Usefulness of combined genetic data in Hungarian families affected by autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary diseases. Mutations of two known genetic loci (PKD1: 16p13.3 and PKD2: 4q21.2) can lead to bilateral renal cysts. The PKD1 locus is the more common ( approximately 85%), with a more severe phenotype. Because of the genetic complexity of ADPKD and the size and complexity of the PKD1 gene, pedigree-based linkage analysis is a useful tool for the genetic diagnosis in families with more than one subject affected. We tested linkage or non-linkage to the closely linked DNA markers flanking the PKD1 (D16S663 and D16S291) and one intragenic D16S3252 and PKD2 (D4S1563 and D4S2462) in 30 ADPKD-affected families, to determine the distributions of alleles and the degree of microsatellite polymorphisms (in 91 patients and 125 healthy subjects). To characterize the markers, used heterozygosity levels, polymorphism information content and LOD scores were calculated. The D16S663 marker included 12 kinds of alleles, while D16S291 had 10 alleles and D16S3252 had 8. D4S1563 had 12 alleles and D4S2462 had 11. In a search for a common ancestral relationship, we considered the patients' alleles with the same repeat number. Only one haplotype was detected in more than one (2) unrelated families. The calculated two-point LOD scores indicated a linkage to PKD1 in 22 families (74%). In four families (13%) with a linkage to PKD2, the patients reached the end-stage renal disease after the age of 65years. One family was linked to neither gene (3%), and in three families (10%) a linkage to both genes was possible. In the latter three families, the numbers of analyzed subjects were small (4-5), and/or some markers were only partially or non-informative. However, the elderly affected family members exhibited the clinical signs of the PKD1 form in these cases. The new Hungarian population genetic information was compared with available data on other populations. PMID:19056484
Endreffy, Emoke; Maróti, Zoltán; Bereczki, Csaba; Túri, Sándor
Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic arteriopathy presenting with migraines, mood disorders, focal neurologic deficits, recurrent ischemic attacks and dementia in young adults. The genesis of this disease relates to missense mutation of the Notch3 gene. We report here a newly identified CADASIL patient and discuss unique vascular lesions observed in the kidney. A 64-year-old female was admitted to our hospital for the investigation of proteinuria, hematuria and progressive neurological abnormalities. Her mother and brother died of cerebral infarction at a relatively young age despite a lack of apparent risk factors for arteriosclerosis. Over the past 4 months before admission, she had suffered from frequent transient ischemic attacks despite appropriate antiplatelet therapy. Blood examination revealed mild renal insufficiency and urinalysis revealed moderate protein excretion and dysmorphic hematuria. Magnetic resonance imaging of the brain revealed multiple infarcts and leukoencephalopathy. Histopathological analysis of the kidney revealed focal segmental mesangial proliferation, the loss and degeneration of arterial medial smooth muscle cells and arterial intimal thickening. Immunofluorescence analysis of glomeruli revealed IgA deposition in the mesangial area. Electron microscope analysis revealed electron-dense deposition also in the mesangial area. In addition, granular osmophilic material (GOM) was observed in the extraglomerular mesangial area and around the vascular smooth muscle cells. Genetic analysis of Notch3 revealed an R141C missense mutation and she was diagnosed with CADASIL complicated with IgA nephropathy. In immunohistological analysis, Notch3 stains were positive in vascular smooth muscle cells of the interlobular arteries and both afferent and efferent arterioles, and weak in the glomerular mesangial area. Antihypertensive treatment using angiotensin II receptor blocker and a low protein diet were initiated, and her urinary protein excretion decreased to 0.2 g/day. However, due to the progression of her neurological abnormalities, she became socially withdrawn. In CADASIL, GOM, abnormal accumulation of Notch3 ectodomain, is thought to induce the degeneration and loss of vascular smooth muscle cells and subsequent intimal thickening. Analysis of our cases provided that these morphological abnormalities were also observed in the CADASIL patient kidney. PMID:17390743
Kusaba, T; Hatta, T; Kimura, T; Sonomura, K; Tanda, S; Kishimoto, N; Kameyama, H; Okigaki, M; Mori, Y; Ishigami, N; Mizuno, T; Nakagawa, M; Matsubara, H
Native nephrectomy in transplant patients with autosomal dominant polycystic kidney disease
INTRODUCTION This study examined the clinical indications and timing for native nephrectomy (NN), together with the associated pathological findings in transplant patients with autosomal dominant polycystic kidney disease (ADPKD) at our institute over a period of 20 years. METHODS A retrospective review was performed of ADPKD patients who had undergone both kidney transplantation and NN. Patients were identified from the kidney transplant database between 1988 and 2008 at Guy's and St Thomas' Hospital and the notes reviewed. All NN specimens were re-reviewed and reported according to current guidelines. RESULTS There were 157 kidney transplants performed for ADPKD (114 cadaveric and 43 living donor). Of these, 31 required NN (28 bilateral). The timing of NN was pre-transplant in 10 cases, at the time of the transplant in 1 case and post-transplant in 20 cases. The indications for NN were urinary tract infection (n=14, 45%), pain (n=12, 39%), tumour suspicion (n=3, 10%), haematuria (n=1, 3%) and space (n=1, 3%). Mortality in this NN series was 3%, with a 65% surgical morbidity rate. The length of hospital stay post-NN was significantly longer with open compared with laparoscopic techniques (p=0.003). There were two renal cell carcinomas (RCCs) in this series. Both patients presented with macroscopic haematuria (bilateral pT1a papillary RCCs in one case and a pT3b clear cell RCC in the other case). The incidence of RCC in this series of ADPKD transplant patients was 1.3%. CONCLUSIONS We have demonstrated that the majority of ADPKD patients do not require NN, with only 20% of our series undergoing this procedure. The timing of NN is variable and dictated by indication. NN was only required to make space for transplantation in one case (combined kidney and pancreas transplant). The main indications for NN were recurrent infection and pain, where NN can provide a successful outcome. Laparoscopic NN can be performed safely in patients with ADPKD. Haematuria in such patients should not be assumed to be of benign origin and requires exclusion of urinary tract malignancy as the incidence of RCC in this population is at least as common as in the general population.
Patel, P; Horsfield, C; Compton, F; Taylor, J; Koffman, G; Olsburgh, J
Short Term Reproducibility of Ambulatory Blood Pressure Monitoring in Autosomal Dominant Polycystic Kidney Disease
Background and objectives Non-dipping defined as a less than 10% decline in night/day ration of blood pressure using 24 hour ambulatory blood pressure monitoring (ABPM) is associated with poor cardiovascular outcomes. However, its reproducibility has been questioned in autosomal dominant polycystic kidney disease (ADPKD). Design, setting, participants and measurements 25 of 29 recruited hypertensive or prehypertensive ADPKD patients completed ABPM on two occasions, 7–15 days apart, on a stable antihypertensive regimen. Day and night time were defined as 6:00–21:59 and 22:00–5:59. Correlation (Corr) and concordance (Conc) coefficients for systolic (SBP), diastolic blood pressure (DBP) and heart rate were determined based on night/day (N:D) and asleep/awake (A:A) periods. Consistency of dipping was assessed by using Cohen's Kappa statistics. Results Mean (±SD) for age, estimated GFR, differences in D-N night SBP and DBP were 43.12 (8.55) years, 63.1 (20.5) mL/min, 11.74(8.2) mmHg and 10.82 (6.4) mmHg respectively. 17/25 subjects (68%) and 18/25 (72%) maintained the same dipping category based on D:N or A:A separation. Cohen's Kappa was 0.34 for D:N and 0.38 for A:A ratios. Correlation and concordance coefficients were 0.89 and 0.88 for daytime SBP, 0.91 and 0.91 for daytime DBP, 0.79 and 0.78 for nighttime SBP, 0.81 and 0.80 for nighttime DBP, 0.58 and 0.56 for N:D ratio of SBP, 0.56 and 0.53 for N:D ratio of DBP. Coefficients for A:A ratios were almost identical to N:D values except for A:A ratios of SBP (0.69 and 0.67) and DBP (0.48 and 0.45). Conclusions Repeated measures of SBP and DBP, 7–15 days apart, are highly correlative and concordant in the studied population but non-dipping, even though predominant, was found to be modestly reproducible.
Rahbari-Oskoui, Frederic F.; Miskulin, Dana; Hogan, Marie; Fielder, Odicie; Torres, Vicente E.; Bost, James; Chapman, Arlene B
Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease
Background Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD). Methods Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit. Results Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6–8.9; P < 0.001) and 2.9 (1.6–5.3; P < 0.001)]. Conclusions Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.
Helal, Imed; McFann, Kim; Reed, Berenice; Yan, Xiang-Dong; Schrier, Robert W.; Fick-Brosnahan, Godela M.
Mechanisms of Disease: insights into X-linked and autosomal-dominant Kallmann syndrome
Kallmann syndrome (KS) is a disorder characterized by hypogonadotropic hypogonadism and anosmia. Although KS is genetically heterogeneous, only two causal genes have been identified to date. These include an X-linked gene that encodes anosmin 1 and an autosomal gene that encodes fibroblast growth factor receptor 1. Mutations in these two genes result in disorders that often include, but are not
John C Gill; Pei-San Tsai
A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series
Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T). Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T). In addition to the clinical diagnosis of both cases, the missense mutation we identified in one allele of the Chloride channel 7 gene could be linked to autosomal dominant osteopetrosis-II because the symptoms appear in late childhood or adolescence. Conclusion In this family, the molecular diagnosis was confirmed after identification of the same mutation in the older son (sibling). Furthermore, we detected that the father and his brother (the uncle) are carriers of the same mutation, whereas the mother and her sister (the aunt) do not carry any mutation of the Chloride channel 7 gene. Thus, the disease penetrance is at least 60% in the family. The mother and father are cousins and a further consanguineous marriage between the aunt and the uncle is not recommended because the dominant allele of the Chloride channel 7 gene will be transferred to the progeny. However, a similar risk is also expected following a marriage between the uncle and an unrelated woman. The p.R409W mutation in the Chloride channel 7 gene has not yet been described in the literature and it possibly has a dominant-negative impact on the protein.
Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts
Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four gen- eration family of Moroccan descent. The maximum lod score (7.19 at recombination fraction ?=0) was obtained for marker D2S2208 near the ?-crystallin gene (CRYG) cluster. Sequencing of the coding regions of
E Nandrot; C Slingsby; A Basak; M Cherif-Chefchaouni; B Benazzouz; Y Hajaji; S Boutayeb; O Gribouval; L Arbogast; A Berraho; M Abitbol; L Hilal
Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations
We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilateral agenesis of the tibia, and club foot. The ultrasonographic picture was consistent with a diagnosis of polycystic kidney disease, either the adult onset autosomal dominant type (ADPKD) or the early onset autosomal recessive form (ARPKD). However, there was
A E Turco; E M Padovani; G P Chiaffoni; B Peissel; S Rossetti; A Marcolongo; L Gammaro; G Maschio; P F Pignatti
An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex.
Mutations in the aquaporin-2 (AQP2) water channel gene cause autosomal recessive nephrogenic diabetes insipidus (NDI). Here we report the first patient with an autosomal dominant form of NDI, which is caused by a G866A transition in the AQP2 gene of one allele, resulting in a E258K substitution in the C-tail of AQP2. To define the molecular cause of NDI in this patient, AQP2-E258K was studied in Xenopus oocytes. In contrast to wild-type AQP2, AQP2-E258K conferred a small increase in water permeability, caused by a reduced expression at the plasma membrane. Coexpression of wild-type AQP2 with AQP2-E258K, but not with an AQP2 mutant in recessive NDI (AQP2-R187C), revealed a dominant-negative effect on the water permeability conferred by wild-type AQP2. The physiologically important phosphorylation of S256 by protein kinase A was not affected by the E258K mutation. Immunoblot and microscopic analyses revealed that AQP2-E258K was, in contrast to AQP2 mutants in recessive NDI, not retarded in the endoplasmic reticulum, but retained in the Golgi compartment. Since AQPs are thought to tetramerize, the retention of AQP2-E258K together with wild-type AQP2 in mixed tetramers in the Golgi compartment is a likely explanation for the dominant inheritance of NDI in this patient.
Mulders, S M; Bichet, D G; Rijss, J P; Kamsteeg, E J; Arthus, M F; Lonergan, M; Fujiwara, M; Morgan, K; Leijendekker, R; van der Sluijs, P; van Os, C H; Deen, P M
Autosomal dominant acute necrotising encephalopathy: a case report with possible disease-expression modification by coincidental homocysteinuria.
We report the case of a 5-year old girl with autosomal dominant acute necrotising encephalopathy (ADANE), who presented with encephalopathy, seizures and coma following a short febrile illness. MR imaging demonstrated characteristic symmetrical, T2 hyper-intense changes involving the external capsule, thalami, brainstem and cerebellum. Unique to this case was co-existing previously unrecognized homocysteinuria due to cystathionine-?-synthase (CBS) deficiency. We discuss metabolic hypotheses of the pathophysiology of ADANE and suggest that the concurrent homocysteinuria may have contributed to the severe phenotype seen in this child, who has been left with profound neurological deficits. PMID:20570537
Gilson, Clare; McFarland, Robert; Forsyth, Rob
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): diagnostic skin biopsy changes determined by electron microscopy.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial vascular disorder associated with migraines, recurrent ischemic strokes, and early-onset multiinfarct dementia. The diagnosis of CADASIL is made ultrastructurally by finding characteristic granular, electron-dense, osmiophilic material attached to vascular smooth muscle cells. These changes have been found in brain, skeletal muscle, nerve, and skin. We describe a woman with CADASIL diagnosed on the basis of brain and skin electronmicroscopic findings. Dermatologists and dermatopathologists need to be aware of this disorder because characteristic electronmicroscopic changes on a skin biopsy specimen are diagnostic. PMID:11100036
Walsh, J S; Perniciaro, C; Meschia, J F
Experimental transmission of an autosomal dominant spongiform encephalopathy: does the infectious agent originate in the human genome?
Marmosets inoculated intracerebrally with brain tissue from a woman with Gerstmann-Straussler syndrome (an autosomal dominant dementia associated with spongiform change and amyloid deposition) developed an encephalopathy indistinguishable from that seen in marmosets inoculated with brain tissue from a typical case of Creutzfeldt-Jakob disease. As in Huntington's disease, in the pedigree of the patient with Gerstmann-Straussler syndrome women who subsequently developed the illness had increased fecundity. The pathogen in human transmissible dementia may arise from a sequence (which itself sometimes confers a selective advantage) located within the human genome.
Baker, H F; Ridley, R M; Crow, T J
No evidence of linkage between the transforming growth factor-alpha gene in families with apparently autosomal dominant inheritance of cleft lip and palate
Eight families have been identified with cleft lip, with or without cleft palate (CL\\/P), inherited in an apparently autosomal dominant manner. Transforming growth factor-alpha (TGFA) has been tested as a candidate gene for clefting in these families. Negative lod scores were generated in an autosomal dominant model with 80% penetrance (Z = -3.152 at theta = 0.05 and Z =
G M Vintiner; S E Holder; R M Winter; S Malcolm
Spectrum and Frequency of Mutations in IMPDH1 Associated with Autosomal Dominant Retinitis Pigmentosa and Leber Congenital Amaurosis
Purpose The purpose of this study was to determine the frequency and spectrum of inosine monophosphate dehydrogenase type I (IMPDH1) mutations associated with autosomal dominant retinitis pigmentosa (RP), to determine whether mutations in IMPDH1 cause other forms of inherited retinal degeneration, and to analyze IMPDH1 mutations for alterations in enzyme activity and nucleic acid binding. Methods The coding sequence and flanking intron/exon junctions of IMPDH1 were analyzed in 203 patients with autosomal dominant RP (adRP), 55 patients with autosomal recessive RP (arRP), 7 patients with isolated RP, 17 patients with macular degeneration (MD), and 24 patients with Leber congenital amaurosis (LCA). DNA samples were tested for mutations by sequencing only or by a combination of single-stranded conformational analysis and by sequencing. Production of fluorescent reduced nicotinamide adenine dinucleotide (NADH) was used to measure enzymatic activity of mutant IMPDH1 proteins. The affinity and the specificity of mutant IMPDH1 proteins for single-stranded nucleic acids were determined by filter-binding assays. Results Five different IMPDH1 variants, Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, and His 372Pro, were identified in eight autosomal dominant RP families. Two additional IMPDH1 variants, Arg105Trp and Asn198Lys, were found in two patients with isolated LCA. None of the novel IMPDH1 mutants identified in this study altered the enzymatic activity of the corresponding proteins. In contrast, the affinity and/or the specificity of single-stranded nucleic acid binding were altered for each IMPDH1 mutant except the Gly324Asp variant. Conclusions Mutations in IMPDH1 account for approximately 2% of families with adRP, and de novo IMPDH1 mutations are also rare causes of isolated LCA. This analysis of the novel IMPDH1 mutants substantiates previous reports that IMPDH1 mutations do not alter enzyme activity and demonstrates that these mutants alter the recently identified single-stranded nucleic acid binding property of IMPDH. Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration.
Bowne, Sara J.; Sullivan, Lori S.; Mortimer, Sarah E.; Hedstrom, Lizbeth; Zhu, Jingya; Spellicy, Catherine J.; Gire, Anisa I.; Hughbanks-Wheaton, Dianna; Birch, David G.; Lewis, Richard A.; Heckenlively, John R.; Daiger, Stephen P.
Investigation of a Family with Autosomal Dominant Dilated Cardiomyopathy Defines a Novel Locus on Chromosome 2q14-q22
Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most frequent indication for heart transplantation in young patients. Probably >25% of DCM cases are of familial etiology. We report here genetic localization in a three-generation German family with 12 affected individuals with autosomal dominant familial DCM characterized by ventricular dilatation, impaired systolic function, and conduction disease. After exclusion of known DCM loci, we performed a whole-genome screen and detected linkage of DCM to chromosome 2q14-q22. Investigation of only affected individuals defines a 24-cM interval between markers D2S2224 and D2S2324; when unaffected individuals are also included, the critical region decreases to 11 cM between markers D2S2224 and D2S112, with a peak LOD score of 3.73 at recombination fraction 0 at D2S2339. The identification of an additional locus for familial autosomal dominant DCM underlines the genetic heterogeneity and may assist in the elucidation of the causes of this disease.
Jung, Martin; Poepping, Imke; Perrot, Andreas; Ellmer, Annette E.; Wienker, Thomas F.; Dietz, Rainer; Reis, Andre; Osterziel, Karl Josef
Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.
Neveling, Kornelia; Martinez-Carrera, Lilian A.; Holker, Irmgard; Heister, Angelien; Verrips, Aad; Hosseini-Barkooie, Seyyed Mohsen; Gilissen, Christian; Vermeer, Sascha; Pennings, Maartje; Meijer, Rowdy; te Riele, Margot; Frijns, Catharina J.M.; Suchowersky, Oksana; MacLaren, Linda; Rudnik-Schoneborn, Sabine; Sinke, Richard J.; Zerres, Klaus; Lowry, R. Brian; Lemmink, Henny H.; Garbes, Lutz; Veltman, Joris A.; Schelhaas, Helenius J.; Scheffer, Hans; Wirth, Brunhilde
A Novel Mutation in the TECTA Gene in a Chinese Family with Autosomal Dominant Nonsyndromic Hearing Loss
TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The ?-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257–262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.
Yu, Fei; Dai, Zhi-Yao; Zhao, Jian-Dong; Lu, Yu; Ji, Fei; Huang, Sha-Sha; Yuan, Yong-Yi; Han, Ming-Yu; Song, Yue-Shuai; Zhu, Yu-Hua; Kang, Dong-Yang; HAN, Dong-Yi; Dai, Pu
Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta
In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.
Gutierrez, Sandra; Torres, Diana; Briceno, Ignacio; Gomez, Ana Maria; Baquero, Eliana
Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis.
Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin. PMID:24339618
Saroja, Aralikatte Onkarappa; Naik, Karkal Ravishankar; Nalini, Atcharayam; Gayathri, Narayanappa
Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis
Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.
Saroja, Aralikatte Onkarappa; Naik, Karkal Ravishankar; Nalini, Atcharayam; Gayathri, Narayanappa
The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
We report the first family of Indian origin known to be affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Seventeen members of the family spanning 3 generations had neurologic syndromes compatible with CADASIL, of whom 5 were genetically confirmed carriers of the Notch3 gene R141C mutation in exon 4 (421(C?T) and 141(Cys?Arg)). Our report highlights that CADASIL not only occurs sporadically in South Asians, but also may account for stroke in South Asians with a strong family history. Furthermore, the similarity of clinical presentations described here to those typical for Caucasian case series suggests that the CADASIL phenotype is preserved across racial groups. PMID:21737310
Yadav, Sunaina; Bentley, Paul; Srivastava, Padma; Prasad, Kameshwar; Sharma, Pankaj
Malignant autosomal dominant frontal lobe epilepsy with repeated episodes of status epilepticus: successful treatment with vagal nerve stimulation.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a familial partial epilepsy syndrome characterized by seizures suggesting a frontal lobe origin occurring predominantly during sleep. Up to a third of patients may have refractory seizures, with repeated episodes of status epilepticus, intellectual disability of variable degree and psychiatric disturbances. We report a patient with ADNFLE, refractory seizures and repeated episodes of life-threatening convulsive status epilepticus who underwent prolonged video-EEG monitoring and was implanted with a vagal nerve stimulator. At 3.5 years of follow-up, a decrease of more than 80% in seizure frequency was achieved, episodes of status were completely controlled and he displayed improved mood and alertness. Vagal nerve stimulation may be considered as therapy for patients with refractory epilepsies of genetic cause, as well as repeated status epilepticus. PMID:20478764
Carreńo, Mar; Garcia-Alvarez, Dionisio; Maestro, Iratxe; Fernández, Santiago; Donaire, Antonio; Boget, Teresa; Rumiŕ, Jordi; Pintor, Luis; Setoain, Xavier
Genetic linkage of autosomal dominant juvenile glaucoma to 1q21-q31 in three affected pedigrees
Glaucoma is a common disorder that results in irreversible damage to the optic nerve, causing absolute blindness. In most cases, the optic nerve is damaged by an elevation of the intraocular pressure that is the result of an abnormality in the normal drainage function of the trabecular meshwork. A family history of glaucoma is an important risk factor for the disease, suggesting that genetic defects predisposing to this condition are likely. Three pedigrees segregating an autosomal dominant juvenile glaucoma demonstrated significant linkage to a group of closely spaced markers on chromosome 1. These results confirm the initial mapping of this disease and suggest that this region on chromosome 1 contains an important locus for juvenile glaucoma. The authors describe recombination events that improve the localization of the responsible gene, reducing the size of the candidate region from 30 to 12 cM. 27 refs., 2 figs., 1 tab.
Wiggs, J.L.; Paglinauan, C.; Fine, A.; Sporn, C.; Lou, D. (Tufts Univ. School of Medicine, Boston, MA (United States)); Haines, J.L. (Harvard Medical School, Boston, MA (United States))
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Neuropathological and in vitro studies of abnormal elastogenesis.
This study was performed on a family of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) subjects. Neuropathological alterations of small arteries consisting in thickening, reduplication and fragmentation of the internal elastic lamella, and granular periodic acid-Schiff-positive material deposited in the arterial media were demonstrated in 1 autopsy case by histochemistry and electron microscopy. This material reacted with a monoclonal antibody anti-elastin (aE), as demonstrated by immunohistochemistry and immunoelectron microscopy. Significant increases of aE-immunoreactivity and elastin mRNA expression were found in cultured skin fibroblasts from 5 family members genetically affected by CADASIL, but not genetically and clinically healthy members. These results suggest that alterations of the elastic apparatus are associated with CADASIL genotype and related to the clinical expression of the disease. PMID:9808276
Caronti, B; Calandriello, L; Francia, A; Scorretti, L; Manfredi, M; Sansolini, T; Pennisi, E M; Calderaro, C; Palladini, G
Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia.
The role of various gene loci was investigated in a family in which familial osteoarthritis (FOA), with onset at an early age, is transmitted as an autosomal dominant mendelian trait. The absence of clinical and radiographic signs of dysplasia and calcium pyrophosphate deposition disease (CPDD) indicates that the basic disease process in this family is osteoarthritis (OA). Genetic linkage analysis of 14 candidate genes resulted in the exclusion of 10 important genes (COL2A1, COL9A1, COL9A2, COL11A1, COL11A2, COMP, the CPDD region, CRTL-1, CRTM, and MMP3). Other relevant genes were not informative in this family. The candidate loci previously identified in FOA and heritable skeletal disorders associated with OA are clearly not involved in the development of the primary FOA phenotype in the family investigated, indicating genetic heterogeneity. Images
Meulenbelt, I; Bijkerk, C; Breedveld, F C; Slagboom, P E
Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia.
The role of various gene loci was investigated in a family in which familial osteoarthritis (FOA), with onset at an early age, is transmitted as an autosomal dominant mendelian trait. The absence of clinical and radiographic signs of dysplasia and calcium pyrophosphate deposition disease (CPDD) indicates that the basic disease process in this family is osteoarthritis (OA). Genetic linkage analysis of 14 candidate genes resulted in the exclusion of 10 important genes (COL2A1, COL9A1, COL9A2, COL11A1, COL11A2, COMP, the CPDD region, CRTL-1, CRTM, and MMP3). Other relevant genes were not informative in this family. The candidate loci previously identified in FOA and heritable skeletal disorders associated with OA are clearly not involved in the development of the primary FOA phenotype in the family investigated, indicating genetic heterogeneity. PMID:9429149
Meulenbelt, I; Bijkerk, C; Breedveld, F C; Slagboom, P E
Dystrophic Epidermolysis Bullosa in Pregnancy: A Case Report of the Autosomal Dominant Subtype and Review of the Literature
Epidermolysis bullosa (EB) is a group of inherited blistering skin diseases that vary widely in their pathogenesis and severity. There are three main categories of EB: simplex, junctional, and dystrophic. This classification is based on the level of tissue separation within the basement membrane zone and this is attributed to abnormalities of individual or several anchoring proteins that form the interlocking network spanning from the epidermis to the dermis underneath. Dystrophic EB results from mutations in COL7A1 gene coding for type VII collagen leading to blister formation within the dermis. Diagnosis ultimately depends on the patient's specific genetic mutation, but initial diagnosis can be made from careful examination and history taking. We present a pregnant patient known to have autosomal dominant dystrophic EB and discuss the obstetrical and neonatal outcome. The paper also reviews the current English literature on this rare skin disorder.
Herrell, Howard
High-resolution cytogenetic analysis of the peripheral blood lymphocytes of patients with autosomal dominant polycystic kidney disease.
High-resolution cytogenetic analysis was performed on peripheral blood lymphocytes of 11 patients (seven women and four men, range 24-56 years) with proven autosomal dominant polycystic kidney disease (ADPKD). A total of 449 metaphases (an average of 41 per patient) were analyzed. In two of the women changes in the karyotype were found in a single cell: del(3), (q21) in one of them and Int.del(6), (q11q21) in the other. Analysis of the remaining patients, including those in which ADPKD was combined with oligophrenia, did not reveal any deviations from the normal karyotype. Therefore, the established chromosome changes are non-specific and of little importance in diagnosing ADPKD. PMID:7927052
Dimitrakov, D
Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): considerations for routine screening and management.
Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease, marked by progressive increase of bilateral renal cysts, resulting in chronic kidney disease (CKD) and often leading to end-stage renal disease (ESRD). Apart from renal cysts, patients often have extra-renal disease, involving the liver, heart and vasculature. Other less common but equally important extra-renal manifestations of ADPKD include diverticular disease, hernias, male infertility and pain. Extra-renal disease burden is often asymptomatic, but may result in increased morbidity and mortality. If the disease burden is significant, screening may prove beneficial. We review the rationale for current screening recommendations and propose some guidelines for screening and management of ADPKD patients. PMID:24215018
Luciano, Randy L; Dahl, Neera K
Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws
A hereditary congenital condition characterized by a fibro-osseous lesion sharing some features with fibrous dysplasia and affecting the middle aspect of the mandible is presented. The condition was initially described as congenital monostotic fibrous dysplasia in two siblings, a male and a female. However, there is sufficient evidence that the disorder is autosomal dominant since it has been encountered in two of four children, both males, of the female propositus and one child, a boy, of the male propositus. All patients presented at birth or right after birth with enlargement of the middle part of the mandible. Radiographs from affected individuals have shown mesomandibular enlargement with irregular trabeculation akin of "ground-glass" appearance. Histologically, samples from all patients revealed woven bone proliferation in a cellular fibroblastic stroma. Interestingly, the originally described siblings, now in their 30s, have no evidence of jaw lesions either radiographically or clinically, thus indicating that the condition is self-limiting or self-resolving. An autosomal dominant mode of inheritance with apparent male predilection is favored. The molecular basis of this condition is currently unknown. However, the location of the lesions in the middle aspect of the mandible suggests dysregulation of Bone Morphogenetic Protein (BMP) signaling since BMPs regulate mandibular morphogenesis in utero, particularly in the medial region as well as postnatal bone remodeling. Immunohistochemical evaluation for a BMP-binding protein Twisted Gastrulation (TWSG1) revealed mosaic pattern of staining, with some cells, including osteoclasts, strongly stained and others exhibiting faint or no staining, thus supporting active regulation of BMP signaling within the lesion. Future investigations will determine if dysregulation of BMP signaling plays a causative role or rather reflects secondary activation of repair mechanisms and/or bone remodeling.
Koutlas, Ioannis G.; Forsman, Cynthia L.; Kyrkanides, Stephanos; Oetting, William S.; Petryk, Anna
Transgenic Mice Expressing Mutant Notch3 Develop Vascular Alterations Characteristic of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22? promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation. Transgenic mice showed no evidence of prominent brain parenchyma damage but demonstrated the two hallmarks of the CADASIL angiopathy, GOM deposits and Notch3 accumulation, within both the cerebral and peripheral arteries. Of interest, arteries of the tail were more severely affected with prominent signs of VSMC degeneration. Time-course analysis of vessel changes revealed that disruption of normal VSMC anchorage to adjacent extracellular matrix and cells, VSMC cytoskeleton changes as well as starting signs of VSMC degeneration, which were detected around 10 months of age, preceded Notch3 and GOM accumulation appearance, which were observed only by 14 to 16 months of age. In conclusion, we have generated transgenic mice that recapitulate the characteristic vascular lesions observed in CADASIL. Our results indicate that Notch3 or GOM accumulation are unlikely to be the prerequisites for the induction of VSMC degeneration and suggest that degeneration of VSMCs may rather be triggered by the disruption of their normal anchorage, based on the important role of adhesion for cell survival.
Ruchoux, Marie Magdeleine; Domenga, Valerie; Brulin, Peggy; Maciazek, Jacqueline; Limol, Sylvie; Tournier-Lasserve, Elisabeth; Joutel, Anne
A novel GJA8 mutation (p.I31T) causing autosomal dominant congenital cataract in a Chinese family
Purpose To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point logarithm of odds (LOD) scores were calculated by using the Linkage software after genotyping. Mutations were detected by DNA sequence analysis of the candidate genes. Effects of amino acid changes on the structure and function of proteins were predicted by bioinformatics analysis. Results Evidence of a linkage was obtained at markers D1S514 (LOD score [Z]=3.48, recombination fraction [?]=0.0) and D1S1595 (Z=2.49, ?=0.0). Haplotype analysis indicated that the cataract gene was close to these two markers. Sequencing of the connexin 50 (GJA8) gene revealed a T>C transition at nucleotide position c.92. This nucleotide change resulted in the substitution of highly conserved isoleucine by threonine at codon 31(I31T). This mutation co-segregated with all affected individuals and was not observed in unaffected or 110 normal unrelated individuals. Bioinformatics analysis showed that a highly conserved region was located at Ile31, and the mutation was predicted to affect the function and secondary structure of the GJA8 protein. Conclusion A novel mutation in GJA8 was detected in a Chinese family with autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype.
Wang, Kaijie; Wang, Binbin; Wang, Jing; Zhou, Shiyi; Yun, Bo; Suo, Peisu; Cheng, Jie; Ma, Xu
Another evidence for a D47N mutation in GJA8 associated with autosomal dominant congenital cataract
Purpose To identify the pathogenic gene mutation in a Chinese family with autosomal dominant inherited nuclear cataract. Methods After obtained informed consent, detailed ophthalmic examinations were performed, genomic DNAs were obtained from eighteen family members in a four-generation Chinese family with five affected. All exons of candidate genes were amplified by polymerase chain reaction (PCR) and were sequenced performed by bidirectional sequencing. The stability of mutation was predicted with Prediction of Protein Mutant Stability changes (PoPMuSiC). The structure homology modeling of the mutant protein was based on Swiss-Model Serve, and its structure was displayed and compared with human connexin26 using the RasMol software. Results By sequencing the encoding regions of the candidate genes, a missence mutation (c.139G>A) was detected in gap junction protein alpha 8 (GJA8) gene, which resulted in the substitution of highly conserved aspartic acid by asparagine at codon 47 (p.D47N). The mutation co-segregated with all patients and was absent in 100 normal Chinese controls. PoPMuSiC analysis showed the change in folding free energy upon mutation (??G) is 0.31 kcal/mol and the mutation p.D47N is destabilizing. The homology modeling showed that the structure of the mutant protein was different with that of human connexin26. Conclusions The study identified a missence mutation (c.139G>A) in GJA8 gene associated with autosomal dominant congenital cataract in a Chinese family. It gave further evidence for GJA8 associated with congenital cataract.
Wang, Li; Luo, Yi; Wen, Wen; Zhang, Shenghai
Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter A? production.
Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of A?42/40 and changed the product line preference of ?-secretase towards A?38 production. In addition, the APP I716F mutation impaired the ?-cleavage and the fourth cleavage of ?-secretase and led to abnormal APP ?-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with ?-secretase cleavage. While all three mutations direct ?-secretase cleavage towards the 48?38 production line, the APP I716F mutation also impaired the ?-cleavage and the fourth cleavage of ?-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation. PMID:24117942
Suárez-Calvet, Marc; Belbin, Olivia; Pera, Marta; Badiola, Nahuai; Magrané, Jordi; Guardia-Laguarta, Cristina; Muńoz, Laia; Colom-Cadena, Martí; Clarimón, Jordi; Lleó, Alberto
A New Locus on Chromosome 12p13.3 for Pseudohypoaldosteronism Type II, an Autosomal Dominant Form of Hypertension
Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2–6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63–129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [?] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, ?=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.
Disse-Nicodeme, Sandra; Achard, Jean-Michel; Desitter, Isabelle; Houot, Anne-Marie; Fournier, Albert; Corvol, Pierre; Jeunemaitre, Xavier
A recurrent missense mutation in GJA3 associated with autosomal dominant cataract linked to chromosome 13q
Purpose To map and identify the genetic defect underlying autosomal dominant cataract segregating in a 5-generation Caucasian American family. Methods Genomic DNA was prepared from blood leukocytes, genotyping was performed using microsatellite markers, and logarithm of the odds (LOD) scores were calculated using the LINKAGE programs. Mutation profiling was performed using direct exon cycle-sequencing and restriction fragment analysis. Protein function effects were evaluated using in silico prediction algorithms. Results Significant evidence of linkage was obtained at marker D13S175 (maximum LOD score [Zmax]=3.67; maximum recombination fraction [?max]=0.04) and D13S1316 (Zmax=2.80, ?max=0.0). Haplotyping indicated that the disease lay in the ~170 Kb physical interval between D13S1316 and D13S175, which contained the gene for gap-junction protein alpha-3 (GJA3) or connexin-46. Sequencing of GJA3 detected a heterozygous transition (c.130G>A) in exon-2 that resulted in gain of an Hsp92 II restriction site. Allele-specific PCR amplification and restriction analysis confirmed that the novel Hsp92 II site co-segregated with cataract in the family but was not detected in 192 normal unrelated individuals. The c.130G>A transition was predicted to result in a non-conservative substitution of valine-to-methionine at codon 44 (p.V44M) with damaging effects on protein function. Conclusions These data confirm GJA3 as one of the most frequently mutated genes that underlie autosomal dominant cataract in humans, and further emphasize the importance of connexin function in maintaining lens transparency.
Bennett, Thomas M.
Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease.
Polycystic liver disease (PCLD, OMIM 174050) is a dominantly inherited condition characterized by the presence of multiple liver cysts of biliary epithelial origin. Fine mapping established linkage to marker D19S581 (Z(max) = 9.65; theta = 0.01) in four large Dutch families with PCLD. We identified a splice-acceptor site mutation (1138-2A-->G) in PRKCSH in three families, and a splice-donor site mutation (292+1G-->C) in PRKCSH segregated completely with PCLD in another family. The protein encoded by PRKCSH, here named hepatocystin, is predicted to localize to the endoplasmic reticulum. These findings establish germline mutations in PRKCSH as the probable cause of PCLD. PMID:12577059
Drenth, Joost P H; te Morsche, Rene H M; Smink, Renate; Bonifacino, Juan S; Jansen, Jan B M J
Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign
Background Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. Methods Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy. Results Rates of rare (minor allele frequency ?0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not. Conclusions We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation.
Strom, Samuel P.
Renal failure in a patient with autosomal dominant polycystic kidney disease and coexisting dermato-polymyositis: first report in the literature.
Autosomal dominant polycystic kidney disease is a multisystem disorder characterized by multiple, bilateral renal cysts and is also associated with cysts in other organs, such as the liver, pancreas, and arachnoid membranes. Dermatomyositis is a disease which mainly involves the skin and muscles, although occasionally other organs are affected. In this report, a 56-year-old male patient with a four-year history of autosomal dominant polycystic kidney disease was presented. Renal failure was exacerbated by a coexisting dermato-polymyositis. Prednisone treatment with hemodialysis improved the situation. This is the first report renal failure in a patient with autosomal dominant polycystic kidney disease and dermato-polymyositis. Images Figure 1 Figure 2 Figure 3
Bahceci, Funda; Sari, Ramazan; Sarikaya, Metin; Atik, Esin; Karincaoglu, Yelda; Sevinc, Alper
Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37. It is characterized by skeletal abnormalities and developmental delay. Here, we report on a girl who had phenotypes of both PH1 and BDMR. PCR-sequencing of the coding regions of AGXT showed a novel missense mutation, c.32C>G (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q. PMID:22821680
Tammachote, Rachaneekorn; Kingsuwannapong, Nelawat; Tongkobpetch, Siraprapa; Srichomthong, Chalurmpon; Yeetong, Patra; Kingwatanakul, Pornchai; Monico, Carla G; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk
Mutation detection in autosomal dominant Hirschsprung disease: SSCP analysis of the RET proto-oncogene
Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction, with an incidence of 1 in 5000. Recently, linkage of an incompletely penetrant, dominant form of HSCR to the pericentromeric region of chromosome 10 was reported, followed by identification of mutations in the RET proto-oncogene in HSCR patients. RET mutations have also been reported in both sporadic and familial forms of three neuroendrocrine tumor syndromes. Unlike the clustered RET mutations observed in these syndromes, the 18 reported HSCR mutations are distributed throughout the extracellular and tryosine kinase domains of RET. In an effort to determine the frequency of RET mutations in HSCR and correlate genotype with phenotype, we have begun to screen for mutations among 80 HSCR probands representing a wide range of phenotypes and pedigree structures. Non-isotopic single strand conformation of polymorphism (SSCP) analysis was carried out using the Pharmacia PhastSystem{trademark}. Initial screening of exons 2 through 6 detected variants in 11 patients not seen in 24 controls. One additional band shift in exon 6 has been observed in both patients and controls. Preliminary sequence analysis has revealed two putative familial mutations in exon 2: a single base pair deletion (49Pro del C 296) and a point mutation that leads to a conservative amino acid substitution (93Gly{r_arrow}Ser). These results suggest that HSCR may be associated with a range of alterations in the coding sequence of the RET extracellular domain. Additional mutations will be described.
Angrist, M.; Bolk, S.; Chakravarti, A. [Case Western Reserve Univ., Cleveland, OH (United States)
Linkage of protection against amyloid fibril formation in the mouse to a single, autosomal dominant gene
Inbred strains of mice provide a model for studies of the pathogenesis of amyloid A (AA) amyloidosis. All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils. In previous studies, we have shown that the CE/J strain, which produces a single, novel apoSAA isoform, apoSAACE/J, is amyloid resistant. In the present study amyloid- resistant CE/J females were mated with amyloid-susceptible CBA/J males to produce F1 hybrid offspring which were then backcrossed to the parental CBA/J mouse strain. Amyloid susceptibility was determined in 30 backcrossed mice 72 h after injection of murine amyloid enhancing factor and silver nitrate. ApoSAA isoforms in plasma were separated by isoelectric focusing gel electrophoresis and visualized after immunoblotting with anti-AA antiserum. Amyloid A fibrils in spleen homogenates were denatured by formic acid and AA protein was quantified by ELISA using anti-mouse apoSAA antibodies. Values < 5 apoSAA equivalent units were considered negative. 13 mice expressed an apoSAA1 and apoSAA2 doublet characteristic of CBA/J mice, whereas 17 mice, expressed the apoSAACE/J isoform codominantly with apoSAA1 and apoSAA2. The correlation of amyloid resistance to expression of the apoSAACE/J isoform was absolute (17/17 were negative; mean score 2.6 +/- 0.17 [standard error of the mean] apoSAA equivalent units) and the correlation between amyloid susceptibility and the expression of apoSAA2/apoSAA1 was also striking (12/13 were amyloid positive; mean score 47.9 +/- 9.0 [standard error of the mean] apoSAA equivalent units (P < 0.001). This is not significantly different from the 50% segregation of apoSAA phenotypes expected for linkage to a single gene. These results indicate that a single gene governs apoSAACE/J expression and thus confers protection against amyloid deposition even in the presence of apoSAA1 and apoSAA2 isoforms and show for the first time that resistance to AA amyloidosis is a dominant trait governed by a single gene.
Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5
Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5682P/+) and homozygous (Trpv5682P/682P) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ?10% of males developed tubulointerstitial nephritis. Trpv5682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5682P/+ and Trpv5682P/682P mice consistent with a trafficking defect. In addition, Trpv5682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria.
Loh, Nellie Y.; Verkaart, Sjoerd; Tammaro, Paolo; Gorvin, Caroline M.; Stechman, Michael J.; Ahmad, Bushra N.; Hannan, Fadil M.; Piret, Sian E.; Evans, Holly; Bellantuono, Ilaria; Hough, Tertius A.; Fraser, William D.; Hoenderop, Joost G. J.; Ashcroft, Frances M.; Brown, Steve D. M.; Bindels, Rene J. M.; Cox, Roger D.; Thakker, Rajesh V.
Higher osteoclastic demineralization and highly mineralized cement lines with osteocalcin deposition in a mandibular cortical bone of autosomal dominant osteopetrosis type II: ultrastructural and undecalcified histological investigations
In this study we report on histological and ultrastructural investigations of the mandibular cortical bone in a case of autosomal dominant osteopetrosis type II complicated by mandibular osteomyelitis. Histologically, there was a marked increase in the number and size of osteoclasts on the inner bone surface. An undecalcified preparation showed a pair of deeply stained (highly demineralized) and stain-phobic (highly
I Semba; T Ishigami; K Sugihara; M Kitano
Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study
BACKGROUND: Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal volume expansion,
Andreas L Serra; Andreas D Kistler; Diane Poster; Marian Struker; Rudolf P Wüthrich; Dominik Weishaupt; Frank Tschirch
Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes?
We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed
Bjarne Udd; Ralf Krahe; Carina Wallgren-Pettersson; Björn Falck; Hannu Kalimo
Search for the Chromosomal Location of Autosomal Dominant Cerebellar Ataxia from Holguin, Cuba: Exclusion from Candidate Regions on Chromosome 4 and 11q
A gene locus for autosomal dominant cerebellar ataxia (ADCA) has been found on chromosome 6p and named spinocerebellar ataxia 1. However, linkage exclusion from chromosome 6p and thus locus heterogeneity has been proven in Cuban ADCA, the largest known collective of ADCA patients, probably due to a founder effect. Two chromosomal regions were analyzed for linkage to Cuban ADCA: chromosome
Suzana Gispert; Christian Nothers; Guillermo Orozco; Georg Auburger
Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.
Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing. PMID:16648378
Eiberg, H; Hansen, L; Kjer, B; Hansen, T; Pedersen, O; Bille, M; Rosenberg, T; Tranebjaerg, L
Genetic Heterogeneity of PKD1 and PKD2 Genes in Iran and Determination of the Genotype\\/Phenotype Correlations in Several Families with Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy, which is characterized by replacement of renal parenchyma with multiple cysts. In Iran, the disease prevalence within the chronic hemodialysis patient population is approximately 8-10%. So far, three genetic loci have been identified to be responsible for ADPKD. Little information is available concerning the pattern of linkage in
Ramin Radpour; Mina Rezaee; Mahdi M. Haghighi; Mina Ohadi; Hossein Najmabadi; Asghar Hajibeigi
An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract
Autosomal dominant congenital cataracts have been associated with mutations of genes encoding several soluble and membrane proteins. By candidate gene screening, we identified a novel mutation in MIP (c.494 G>A) that segregates with a congenital lamellar cataract within a South Indian family and causes the replacement of a highly conserved glycine by aspartate (G165D) within aquaporin0 (AQP0). Unlike wild type AQP0, expression of AQP0-G165D in Xenopus oocytes did not facilitate swelling in hypotonic medium. In transfected HeLa cells, wild type AQP0 localized at the plasma membrane while AQP0-G165D was retained within the secretory pathway, and localized mainly within the endoplasmic reticulum. These results suggest that mutation of this conserved glycine residue leads to improper trafficking of AQP0-G165D and loss of water channel function. They emphasize the importance of AQP0 for maintenance of lens transparency and identify a critical residue that is conserved among aquaporins, but has not previously been associated with disease-associated replacement.
Kumar, G. Senthil; Kyle, John W.; Minogue, Peter J.; Kumar, K. Dinesh; Vasantha, K.; Berthoud, Viviana M.; Beyer, Eric C.; Sathiyavedu, Santhiya T.
Identification and Functional Analysis of GJA8 Mutation in a Chinese Family with Autosomal Dominant Perinuclear Cataracts
Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that causes visual impairment and childhood blindness. The purpose of this study was to identify the genetic defect associated with autosomal dominant congenital perinuclear cataract in a Chinese family. A detailed family history and clinical data of the family were recorded, and candidate gene sequencing was performed to screen for mutation-causing disease in our study. Direct sequencing revealed a c.601G>A (p.E201K) transversion in exon 2 of GJA8. This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members or 100 unrelated controls. The function and mechanism of novel GJA8 point mutation E201K in Chinese patients were then investigated in this study. We found E201K aberrantly located in cytoplasm and prevented its location in the plasma membrane. Induction of E201K expression led to a decrease in cell growth and viability by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Our study provides important evidence that GJA8 is a disease-causing gene for congenital cataract and that mutation of GJA8 has a potential causative effect.
Li, Qian; Guan, Lina; Zhang, Huiling; E, Dandan; Zhang, Lei; Zhu, Siquan; Ma, Xu
Urodynamic evaluation of patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24
OBJECTIVES—There are at least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP). Lower urinary tract symptoms are often present but have not been described in a homogeneous patient population. In this study lower urinary tract symptoms, cystometrical, and neurophysiological characteristics are described in patients with ADPSP linked to chromosome 2p21-p24.?METHODS—Lower urinary tract symptoms were recorded at an interview and according to a formalised questionnaire. Eleven patients were clinically evaluated and cystometry, measurements of the cutaneous perception threshold, bulbocavernosus reflex latency, and somatosensory evoked potentials (SSEPs) of the pudendal nerve were performed.?RESULTS—All patients experienced urinary urgency or urge incontinence. Rectal urgency and sexual dysfunction were reported by most patients. The cystometrical findings showed a mixed pattern of bladder dysfunction. The SSEPs were normal in all but the bulbocavernosus reflex latency was significantly prolonged in seven patients and the cutaneous perception threshold was raised in five patients.?CONCLUSIONS—Lower urinary tract symptoms and probably also bowel and sexual dysfunction in patients with ADPSP linked to chromosome 2p21-p24 are due to a combination of somatic and autonomic nervous system involvement which support the proposed multisystem affection in ADPSP linked to chromosome 2p21-p24.??
Jensen, L; Gerstenberg, T; Kallestrup, E; Koefoed, P; Nordling, J; Nielsen, J
A novel arginine vasopressin-neurophysin II mutation causes autosomal dominant neurohypophyseal diabetes insipidus and morphologic pituitary changes.
To determine the genetic basis of autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) in a Cypriot family, we ascertained and studied a large, four-generation kindred in which all participating family members had arginine vasopressin-neurophysin II (AVP-NP-II) gene analyses done. A G to A transition was found by DNA sequence analysis at position 1773 (G1773A) of the AVP-NPII gene which is predicted to encode a substitution of tyrosine for cysteine in codon 59 (CYS59TYR). The mutation was confirmed by restriction endonuclease analysis of PCR amplification products that contain the corresponding segment of the AVP-NPII gene. To clarify the morphologic status of the pituitaries of family members, 12 affected and 3 nonaffected members had magnetic resonance imaging (MRI) studies. The bright spot of the posterior pituitary lobe was completely absent in 75% and faintly identified in 25% of the affected members who were examined with MRI. We conclude that (1) a novel G1773A transition in exon 2 of the AVP-NPII gene causes ADNDI in the large Cypriot kindred studied, (2) this mutation is predicted to encode a CYS59TYR substitution in NPII, and (3) MRI studies of the posterior pituitary lobes of affected family members show either a decreased intensity or a complete absence of the bright spot in all cases studied. PMID:11150885
Skordis, N; Patsalis, P C; Hettinger, J A; Kontou, M; Herakleous, E; Krishnamani, M R; Phillips, J A
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Genetic Cause of Cerebral Small Vessel Disease
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the Notch3 gene. The exact prevalence of this disorder was unknown currently, and the number of reported CADASIL families is steadily increasing as the clinical picture and diagnostic examinations are becoming more widely known. The main clinical manifestations are recurrent stroke, migraine, psychiatric symptoms, and progressive cognitive impairment. The clinical course of CADASIL is highly variable, even within families. The involvement of the anterior temporal lobe and the external capsule on brain magnetic resonance imaging was found to have high sensitivity and specificity in differentiating CADASIL from the much more common sporadic cerebral small-vessel disease (SVD). The pathologic hallmark of the disease is the presence of granular osmiophilic material in the walls of affected vessels. CADASIL is a prototype single-gene disorder that has evolved as a unique model for studying the mechanisms underlying cerebral SVD. At present, the incidence and prevalence of CADASIL seem to be underestimated due to limitations in clinical, neuroradiological, and genetic diagnoses of this disorder.
Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue. PMID:20642692
Canaud, G; Knebelmann, B; Harris, P C; Vrtovsnik, F; Correas, J-M; Pallet, N; Heyer, C M; Letavernier, E; Bienaimé, F; Thervet, E; Martinez, F; Terzi, F; Legendre, C
Identification of a Locus for Autosomal Dominant Polycystic Liver Disease, on Chromosome 19p13.2-13.1
Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of polycystic liver disease in the presence or absence of ADPKD are indistinguishable, raising the possibility that the pathogenetic mechanisms in the diseases are interrelated. We ascertained two large families with polycystic liver disease without kidney cysts and performed a genomewide scan for genetic linkage. A causative gene, PCLD, was mapped to chromosome 19p13.2-13.1, with a maximum LOD score of 10.3. Haplotype analysis refined the PCLD interval to 12.5 cM flanked by D19S586/D19S583 and D19S593/D19S579. The discovery of genetic linkage will facilitate diagnosis and study of this underdiagnosed disease entity. Identification of PCLD will be instrumental to an understanding of the pathogenesis of cyst formation in the liver in isolated PCLD and in ADPKD.
Reynolds, David M.; Falk, Cathy T.; Li, Airong; King, Bernard F.; Kamath, Patrick S.; Huston III, John; Shub, Clarence; Iglesias, Diana M.; Martin, Rodolfo S.; Pirson, Yves; Torres, Vicente E.; Somlo, Stefan
Successful living donor liver transplantation for polycystic liver in a patient with autosomal-dominant polycystic kidney disease.
Orthotopic liver transplantation has been recommended for patients with disabling polycystic liver disease (PCLD). Because of the shortage of cadaveric donors, living donor liver transplantation (LDLT) has been developed as an alternative. We describe the case of a woman with PCLD as an extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) who was successfully palliated by LDLT. The patient was a 48-year-old woman with abdominal distention. Computed tomography showed a massively enlarged liver containing innumerable cysts, as well as bilateral kidney cysts. Hepatic and renal functions were well preserved. Genetic analysis of the family did not exclude linkage to the PKD1 locus. Two and a half years after the first examination, the patient reported severely disabling symptoms caused by the PCLD. Living donor liver transplantation was performed using a right-lobe graft. The recipient and donor were both well 8 months after the transplantation. The excised liver weighed 7.4 kg, and the histopathology revealed multiple cysts and von Meyenburg complexes in the portal areas. PMID:11500614
Takegoshi, K; Tanaka, K; Nomura, H; Miyagi, K; Taira, S; Takayanagi, N
Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1.
Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of polycystic liver disease in the presence or absence of ADPKD are indistinguishable, raising the possibility that the pathogenetic mechanisms in the diseases are interrelated. We ascertained two large families with polycystic liver disease without kidney cysts and performed a genomewide scan for genetic linkage. A causative gene, PCLD, was mapped to chromosome 19p13.2-13.1, with a maximum LOD score of 10.3. Haplotype analysis refined the PCLD interval to 12.5 cM flanked by D19S586/D19S583 and D19S593/D19S579. The discovery of genetic linkage will facilitate diagnosis and study of this underdiagnosed disease entity. Identification of PCLD will be instrumental to an understanding of the pathogenesis of cyst formation in the liver in isolated PCLD and in ADPKD. PMID:11047756
Reynolds, D M; Falk, C T; Li, A; King, B F; Kamath, P S; Huston, J; Shub, C; Iglesias, D M; Martin, R S; Pirson, Y; Torres, V E; Somlo, S
Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients.
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is caused by mutations in PKD1 or PKD2. The molecular diagnosis of ADPKD is complicated by extensive allelic heterogeneity and particularly by the presence of six highly homologous sequences of PKD1 exons 1-33. Here, we screened PKD1 and PKD2 for both conventional mutations and gross genomic rearrangements in up to 700 unrelated ADPKD patients--the largest patient cohort to date--by means of direct sequencing, followed by quantitative fluorescent multiplex polymerase chain reaction or array-comparative genomic hybridization. This resulted in the identification of the largest number of new pathogenic mutations (n = 351) in a single publication, expanded the spectrum of known ADPKD pathogenic mutations by 41.8% for PKD1 and by 23.8% for PKD2, and provided new insights into several issues, such as the population-dependent distribution of recurrent mutations compared with founder mutations and the relative paucity of pathogenic missense mutations in the PKD2 gene. Our study, together with others, highlights the importance of developing novel approaches for both mutation detection and functional validation of nondefinite pathogenic mutations to increase the diagnostic value of molecular testing for ADPKD. PMID:22508176
Audrézet, Marie-Pierre; Cornec-Le Gall, Emilie; Chen, Jian-Min; Redon, Sylvia; Quéré, Isabelle; Creff, Joelle; Bénech, Caroline; Maestri, Sandrine; Le Meur, Yann; Férec, Claude
High-Resolution En Face Images of Microcystic Macular Edema in Patients with Autosomal Dominant Optic Atrophy
The purpose of this study was to investigate the characteristics of microcystic macular edema (MME) determined from the en face images obtained by an adaptive optics (AO) fundus camera in patients with autosomal dominant optic atrophy (ADOA) and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT). Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL) thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL) of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL.
Kikuchi, Sachiko; Kabuto, Takenori; Mizota, Atsushi; Yamaki, Kunihiko; Takahashi, Hiroshi
Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression
ABSTRACT Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
Giorgio, Elisa; Rolyan, Harshvardhan; Kropp, Laura; Chakka, Anish Baswanth; Yatsenko, Svetlana; Gregorio, Eleonora Di; Lacerenza, Daniela; Vaula, Giovanna; Talarico, Flavia; Mandich, Paola; Toro, Camilo; Pierre, Eleonore Eymard; Labauge, Pierre; Capellari, Sabina; Cortelli, Pietro; Vairo, Filippo Pinto; Miguel, Diego; Stubbolo, Danielle; Marques, Lourenco Charles; Gahl, William; Boespflug-Tanguy, Odile; Melberg, Atle; Hassin-Baer, Sharon; Cohen, Oren S; Pjontek, Rastislav; Grau, Armin; Klopstock, Thomas; Fogel, Brent; Meijer, Inge; Rouleau, Guy; Bouchard, Jean-Pierre L; Ganapathiraju, Madhavi; Vanderver, Adeline; Dahl, Niklas; Hobson, Grace; Brusco, Alfredo; Brussino, Alessandro; Padiath, Quasar Saleem
Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP?). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP? in neuronal cells. The resulting depletion of functional CSP? might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP? in humans and demonstrates the need for detailed investigation of CSP? in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.
Noskova, Lenka; Stranecky, Viktor; Hartmannova, Hana; Pristoupilova, Anna; Baresova, Veronika; Ivanek, Robert; Hulkova, Helena; Jahnova, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynela, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav
Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.
Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD. PMID:18818683
Consugar, Mark B; Wong, Wai C; Lundquist, Patrick A; Rossetti, Sandro; Kubly, Vickie J; Walker, Denise L; Rangel, Laureano J; Aspinwall, Richard; Niaudet, W Patrick; Ozen, Seza; David, Albert; Velinov, Milen; Bergstralh, Eric J; Bae, Kyongtae T; Chapman, Arlene B; Guay-Woodford, Lisa M; Grantham, Jared J; Torres, Vicente E; Sampson, Julian R; Dawson, Brian D; Harris, Peter C
A Novel PRPF31 Mutation in a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa and Macular Degeneration
Purpose This study was intended to identify the disease causing genes in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. Methods A genome scan analysis was conducted in this family for disease gene preliminary mapping. Snapshot analysis of selected SNPs for two-point LOD score analysis for candidate gene filter. Candidate gene PRPF31 whole exons' sequencing was executed to identify mutations. Results A novel nonsense mutation caused by an insertion was found in PRPF31 gene. All the 19 RP patients in 1085 family are carrying this heterozygous nonsense mutation. The nonsense mutation is in PRPF31 gene exon9 at chr19:54629961-54629961, inserting nucleotide "A" that generates the coding protein frame shift from p.307 and early termination at p.322 in the snoRNA binding domain (NOP domain). Conclusion This report is the first to associate PRPF31 gene's nonsense mutation and adRP and JMD. Our findings revealed that PRPF31 can lead to different clinical phenotypes in the same family, resulting either in adRP or syndrome of adRP and JMD. We believe our identification of the novel "A" insertion mutation in exon9 at chr19:54629961-54629961 in PRPF31 can provide further genetic evidence for clinical test for adRP and JMD.
Zheng, Hong; Liu, Xiaoqi; Yang, Jiyun; Shi, Yi; Lin, Ying; Gong, Bo; Zhu, Xianjun; Ma, Shi; Qiao, Lifeng; Lin, He; Cheng, Jing; Yang, Zhenglin
Percutaneous Nephrolithotomy in Autosomal Dominant Polycystic Kidney Disease: Is it Different from Percutaneous Nephrolithotomy in Normal Kidney?
Objectives Nephrolithiasis has been reported in 20-28% of patients, of whom 50% are symptomatic for stone disease and 20% require definite urologic intervention. The management of nephrolithiasis includes oral alkali dissolution therapy, extracorporeal shock wave lithotripsy and surgical treatment. In such patients, percutaneous nephrolithotomy (PNL) as a method of stone treatment has been reported in few cases with limited experience. The aim of this study is to present our experience of PNL in autosomal dominant polycystic kidney disease (ADPKD) and assessing the outcome results. Material and Methods From 2002 to 2011, 22 patients (26 renal units) suffering from ADPKD with stone were managed by PNL. Demographic characteristics, operative parameters and postoperative complications were recorded and analysed. Result The overall success rate of PNL was 82.1% and PNL with extracorporeal shock wave lithotripsy for clinically significant residual fragments was 92.85% respectively. The hematuria required blood transfusion (n = 9), postoperative fever due to cyst infection (n = 4) and paralytic ileus (n = 3) were recorded. Conclusion The PNL in ADPKD PNL is safe and effective but have more postoperative complications such as bleeding requiring transfusions, fever due to cyst infection and paralytic ileus.
Singh, Vishwajeet; Sinha, Rahul Janak; Gupta, Dheeraj Kumar
Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310
Böhm, Johann; Biancalana, Valérie; Dechene, Elizabeth T; Bitoun, Marc; Pierson, Christopher R; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S; Barger, Melissa A; Mahoney, Lane J; Kang, Peter B; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Bomme Ousager, Lilian; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S B; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Poza Aldea, Juan José; Michel, Fabrice; Furby, Alain; Llona, Jose E Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A H; Smith, Stephen A; Roggenbuck, Jennifer; Crowe, Carol A; Brennan Spitale, Allison; Johal, Sheila C; Amato, Anthony A; Demmer, Laurie A; Jonas, Jessica; Darras, Basil T; Bird, Thomas D; Laurino, Mercy; Welt, Selman I; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H; Laporte, Jocelyn
Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
Bohm, Johann; Biancalana, Valerie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurelia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan Jose Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valerie; Beroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn
A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26)
Linkage analysis in a multigenerational family with autosomal dominant hearing loss yielded a chromosomal localisation of the underlying genetic defect in the DFNA20/26 locus at 17q25-qter. The 6-cM critical region harboured the ?-1-actin (ACTG1) gene, which was considered an attractive candidate gene because actins are important structural elements of the inner ear hair cells. In this study, a Thr278Ile mutation was identified in helix 9 of the modelled protein structure. The alteration of residue Thr278 is predicted to have a small but significant effect on the ? 1 actin structure owing to its close proximity to a methionine residue at position 313 in helix 11. Met313 has no space in the structure to move away. Moreover, the Thr278 residue is highly conserved throughout eukaryotic evolution. Using a known actin structure the mutation could be predicted to impair actin polymerisation. These findings strongly suggest that the Thr278Ile mutation in ACTG1 represents the first disease causing germline mutation in a cytoplasmic actin isoform.
van Wijk, E; Krieger, E; Kemperman, M; De Leenheer, E M R; Huygen, P; Cremers, C; Cremers, F; Kremer, H
Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.
The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy. PMID:14961560
Baris, Olivier; Delettre, Cécile; Amati-Bonneau, Patrizia; Surget, Marie-Odile; Charlin, Jean-François; Catier, Antoine; Derieux, Laurence; Guyomard, Jean-Laurent; Dollfus, Hélčne; Jonveaux, Philippe; Ayuso, Carmen; Maumenee, Irene; Lorenz, Birgit; Mohammed, Shehla; Tourmen, Yves; Bonneau, Dominique; Malthičry, Yves; Hamel, Christian; Reynier, Pascal
A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy
Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log10 odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription–PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of ?3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, G-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.
Bonnemann, Carsten G.; Cox, Gerald F.; Shapiro, Frederic; Wu, Jiann-Jiu; Feener, Chris A.; Thompson, Teryl G.; Anthony, Douglas C.; Eyre, David R.; Darras, Basil T.; Kunkel, Louis M.
Exon Sequencing of PKD1 Gene in an Iranian Patient with Autosomal-Dominant Polycystic Kidney Disease.
Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with the incidence of 1 in 1,000 births. ADPKD is genetically heterogeneous with two genes identified: PKD1 (16p13.3, 46 exons) and PKD2 (4q21, 15 exons). Eighty five percent of the patients with ADPKD have at least one mutation in the PKD1 gene. Genetic studies have demonstrated an important allelic variability among patients, but very few data are known about the genetic variation among Iranian populations. Methods: In this study, exon direct sequencing of PKD1 was performed in a seven-year old boy with ADPKD and in his parents. The patient's father was ADPKD who was affected without any kidney dysfunction, and the patient's mother was congenitally missing one kidney. Results: Molecular genetic testing found a mutation in all three members of this family. It was a missense mutation GTG>ATG at position 3057 in exon 25 of PKD1. On the other hand, two novel missense mutations were reported just in the 7-year-old boy: ACA>GCA found in exon 15 at codon 2241 and CAC>AAC found in exon 38 at codon 3710. For checking the pathogenicity of these mutations, exons 15, 25, and 38 of 50 unrelated normal cases were sequenced. Conclusion: our findings suggested that GTG>ATG is a polymorphism with high frequency (60%) as well as ACA>GCA and CAC>AAC are polymorphisms with frequencies of 14% and 22%, respectively in the population of Southwest Iran. PMID:24842140
Hafizi, Atousa; Khatami, Saeid Reza; Galehdari, Hamid; Shariati, Gholamreza; Saberi, Ali Hossein; Hamid, Mohammad
Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP).
Autosomal-dominant hereditary spastic paraplegia (AD-HSP) is a crippling neurodegenerative disease for which effective treatment or cure remains unknown. Victims experience progressive mobility loss due to degeneration of the longest axons in the spinal cord. Over half of AD-HSP cases arise from loss-of-function mutations in spastin, which encodes a microtubule-severing AAA ATPase. In Drosophila models of AD-HSP, larvae lacking Spastin exhibit abnormal motor neuron morphology and function, and most die as pupae. Adult survivors display impaired mobility, reminiscent of the human disease. Here, we show that rearing pupae or adults at reduced temperature (18°C), compared with the standard temperature of 24°C, improves the survival and mobility of adult spastin mutants but leaves wild-type flies unaffected. Flies expressing human spastin with pathogenic mutations are similarly rescued. Additionally, larval cooling partially rescues the larval synaptic phenotype. Cooling thus alleviates known spastin phenotypes for each developmental stage at which it is administered and, notably, is effective even in mature adults. We find further that cold treatment rescues larval synaptic defects in flies with mutations in Flower (a protein with no known relation to Spastin) and mobility defects in flies lacking Kat60-L1, another microtubule-severing protein enriched in the CNS. Together, these data support the hypothesis that the beneficial effects of cold extend beyond specific alleviation of Spastin dysfunction, to at least a subset of cellular and behavioral neuronal defects. Mild hypothermia, a common neuroprotective technique in clinical treatment of acute anoxia, might thus hold additional promise as a therapeutic approach for AD-HSP and, potentially, for other neurodegenerative diseases. PMID:24906373
Baxter, Sally L; Allard, Denise E; Crowl, Christopher; Sherwood, Nina Tang
Neutrophil-to-lymphocyte ratio, insulin resistance, and endothelial dysfunction in patients with autosomal dominant polycystic kidney disease
Endothelial dysfunction (ED), insulin resistance (IR), and inflammation are risk factors for increased cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD). ADPKD patients may have increased carotid intima-media thickness (CIMT) and decreased coronary flow velocity reserve (CFVR). The neutrophil-to-lymphocyte ratio (NLR) was introduced as a marker to determine inflammation in various disorders. We aimed to investigate the relationship between NLR and IR, CFVR, CIMT, and the left ventricular mass index (LVMI) in normotensive ADPKD patients. Twentynine ADPKD patients (age 38.8 ± 10.2 years; 8 men and 21 women) and 19 healthy controls (age 33.8 ± 7.4 years; 8 men and 11 women) were included in this cross-sectional study. CFVR was calculated with echocardiography as the ratio of hyperemic to baseline diastolic peak coronary flow velocities. CIMT was measured in the distal common carotid artery by using a 10-MHz linear echocardiography probe. HOMA-IR was calculated NLR was calculated as the ratio of the neutrophil and lymphocyte counts. Age, sex, body mass index, and levels of glucose, creatinine, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, C-reactive protein (CRP), microalbuminuria, and creatinine clearance were similar between ADPKD patients and healthy subjects. NLR, CIMT, LVMI, and HOMA-IR were significantly higher and CFVR values were significantly lower in patients with ADPKD compared to that in healthy subjects. NLR showed positive correlation with CIMT, HOMA, insulin, glucose, and HDL cholesterol levels, while it was inversely correlated with CFVR and albumin level in all subjects. In patients with ADPKD, NLR showed positive correlation with HDL cholesterol level and inverse correlation with LVMI and albumin level. NLR that was found to be increased in patients with ADPKD may be a readily available marker of inflammation and ED.
Turkmen, K.; Tufan, F.; Selcuk, E.; Akp?nar, T.; Oflaz, H.; Ecder, T.
Non-Image-Forming Light Driven Functions Are Preserved in a Mouse Model of Autosomal Dominant Optic Atrophy
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.
Perganta, Georgia; Barnard, Alun R.; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H.; MacLaren, Robert E.; Votruba, Marcela; Sekaran, Sumathi
Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies. PMID:23409176
Perganta, Georgia; Barnard, Alun R; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H; MacLaren, Robert E; Votruba, Marcela; Sekaran, Sumathi
Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4?), c.652C>T (p.Arg218?), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218?) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
Basmanav, F. Buket; Oprisoreanu, Ana-Maria; Pasternack, Sandra M.; Thiele, Holger; Fritz, Gunter; Wenzel, Jorg; Grosser, Leopold; Wehner, Maria; Wolf, Sabrina; Fagerberg, Christina; Bygum, Anette; Altmuller, Janine; Rutten, Arno; Parmentier, Laurent; El Shabrawi-Caelen, Laila; Hafner, Christian; Nurnberg, Peter; Kruse, Roland; Schoch, Susanne; Hanneken, Sandra; Betz, Regina C.
Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease
Background Urinary tract infection (UTI) occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD). However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. Methods We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. Results With a mean follow-up duration of 65.3 months, 176 (68.8%) out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01) and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension). The annual change in estimated glomerular filtration rate (?eGFR) was significantly larger in magnitude in group B than in group A (-2.7±4.56 vs. -1.17±5.8, respectively; P=0.01). Age and Group B found to be the independent variables for ?eGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001). Conclusions Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.
Clinical Characteristics and Disease Predictors of a Large Chinese Cohort of Patients with Autosomal Dominant Polycystic Kidney Disease
Objective Autosomal dominant polycystic kidney disease (ADPKD) is a relentlessly progressing form of chronic kidney disease for which there is no cure. The aim of this study was to characterize Chinese patients with ADPKD and to identify the factors which predict cyst growth and renal functional deterioration. Methods To analyze disease predicting factors we performed a prospective longitudinal observational study in a cohort of 541 Chinese patients with ADPKD and an eGFR ?30 ml/min/1.73 m2. Patients were followed clinically and radiologically with sequential abdominal magnetic resonance imaging (MRI). Clinical characteristics and laboratory data were related to changes in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). A linear regression model was developed to analyze the factors which determine eGFR and TKV changes. Results The age range of this unselected cohort ranged from 4 to 77 years. Median follow-up time was 14.3±10.6 months. Although inter-individual differences in eGFR and TKV were large, there was a consistent link between these two parameters. Baseline log10-transformed TKV and urinary protein/creatinine ratio were identified as the major predictors for a faster eGFR decline and were associated with a higher TKV growth rate. Interestingly, a lower thrombocyte count correlated significantly with lower eGFR (r?=?0.222) and higher TKV (r?=?0.134). Conclusions This large cohort of Chinese patients with ADPKD provides unique epidemiological data for comparison with other cohorts of different ethnicity. In Chinese patients we identified a lower thrombocyte count as a significant predictor of disease progression. These results are important for the design of future clinical trials to retard polycystic kidney disease progression.
Wang, Xueqi; Yu, Shengqiang; Li, Lin; Dai, Bing; Mao, Zhiguo; Sun, Lijun; Xu, Chenggang; Rong, Shu; Tang, Mengjun; Zhao, Hongbo; Liu, Hongchao; Serra, Andreas L.; Graf, Nicole; Liu, Shiyuan; Wuthrich, Rudolf P.; Mei, Changlin
Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multi-Ethnic Patient Cohort
Background Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low density lipoprotein-cholesterol (LDL-C), is caused by variants in at least three different genes:LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin-like kexin type 9 (PCSK9). There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multi-ethnic patient cohort from lipid clinics in a large urban U.S. city. Methods and Results A total of 38 males and 53 females, age 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR, and in selected exons of APOB and PCSK9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in APOB in one patient. The remaining 60 patients (65%) had "unexplained ADH." A higher proportion of African Americans (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had "unexplained ADH." As compared to patients with LDLR variants, those with "unexplained ADH" had lower levels of LDL-C (292 ± 47vs 239 ± 42 mg/dL, respectively; p < 0.0001) and higher levels of HDL-cholesterol (45 ± 12vs 54 ± 13 mg/dL, respectively, p = 0.003). Conclusions Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as African Americans.
Ahmad, Zahid; Adams-Huet, Beverley; Chen, Chiyaun; Garg, Abhimanyu
A hypermorphic I?B? mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKK?, the regulatory subunit of the I?B kinase (IKK) complex. IKK normally phosphorylates the I?B-inhibitors of NF-?B at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-?B complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of I?B?. This mutation is gain-of-function, as it enhances the inhibitory capacity of I?B? by preventing its phosphorylation and degradation, and results in impaired NF-?B activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1?, and IL-18), and TNFR (TNF-?, LT?1/?2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-?B signaling pathway.
Courtois, Gilles; Smahi, Asma; Reichenbach, Janine; Doffinger, Rainer; Cancrini, Caterina; Bonnet, Marion; Puel, Anne; Chable-Bessia, Christine; Yamaoka, Shoji; Feinberg, Jacqueline; Dupuis-Girod, Sophie; Bodemer, Christine; Livadiotti, Susanna; Novelli, Francesco; Rossi, Paolo; Fischer, Alain; Israel, Alain; Munnich, Arnold; Deist, Francoise Le; Casanova, Jean-Laurent
Risk of intracranial hemorrhage associated with autosomal dominant polycystic kidney disease in patients with end stage renal disease
Background An analysis of intracranial hemorrhage (ICH) in a national sample of autosomal dominant polycystic kidney disease (ADPKD) patients receiving long-term dialysis has not been reported. It is often assumed that patients with ADPKD are not at increased risk of ICH after starting dialysis. We hypothesized that patients with ADPKD would have a higher subsequent risk of ICH even after the start of chronic dialysis. Methods Retrospective cohort study of Medicare primary patients with and without ADPKD in the United States Renal Data System (USRDS), initiated on chronic dialysis or transplanted between 1 January 1999 and 3 July 2009, and followed until 31 December 2009. Covariates included age, gender, race, prior stroke, diabetes mellitus, dialysis modality, body mass index, serum albumin and other co-morbid conditions from the Medical Evidence Form. Primary outcome was ICH, based on inpatient and outpatient Medicare claims, and all-cause mortality. Kaplan-Meier analysis was used for unadjusted assessment of time to events. Cox regression was used for assessment of factors associated with ICH and mortality. We performed competing risk regression using kidney transplant and death as competing risks. Kidney transplant was also modeled as a time-dependent covariate in Cox regression. Results Competing risk regression demonstrated that ADPKD had a subhazard ratio 2.97 for ICH (95% CI 2.27-3.89). Adjusted Cox analysis showed that ADPKD patients had an AHR for death of 0.59 vs. non-ADPKD patients (95% CI 0.57-0.61). Conclusions ADPKD is a significant risk factor for ICH among patients on maintenance dialysis. Our Medicare primary cohort was older than in previous studies of intracranial aneurysm rupture among ADPKD patients. There are also limitations inherent to using the USRDS database.
Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit?
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis of nephroangiosclerosis through functional impairment of renal microcirculation or primary Notch3-related vascular disease. PMID:18572291
Guerrot, Dominique; François, Arnaud; Boffa, Jean-Jacques; Boulos, Nada; Hanoy, Melanie; Legallicier, Bruno; Triquenot-Bagan, Aude; Guyant-Marechal, Lucie; Laquerriere, Annie; Freguin-Bouilland, Caroline; Ronco, Pierre; Godin, Michel
Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology.
Autosomal dominant osteopetrosis type II (ADO II) is a rare, heritable bone disorder characterized by a high bone mass and insufficient osteoclast activity. Mutations in the CLCN7 gene have been reported to cause ADO II. To gain novel insights into the pathways dysregulated in ADOII osteoclasts, we identified changes in gene expression in osteoclasts from patients with a heterozygous mutation of CLCN7. To do this, we carried out a transcriptomic study comparing gene expression in the osteoclasts of patients with ADO II and healthy donors. Our data show that, according to our selection criteria, 182 genes were differentially expressed in osteoclasts from patients and controls. From the 18 displaying the highest change in microarray, we confirmed differential expression for seven by qPCR. Although two of them have previously been found to be expressed in osteoclasts (ITGB5 and SERPINE2), the other five (CES1 (carboxyl esterase 1), UCHL1 (ubiquitin carboxy-terminal esterase L1, also known as ubiquitin thiolesterase), WARS (tryptophanyl-tRNA synthetase), GBP4 (guanylate-binding protein 4), and PRF1) are not yet known to have a role in this cell type. At the protein level, we confirmed elevated expression of ITGB5 and reduced expression of WARS, PRF1, and SERPINE2. Transfection of ClC-7 harboring the G215R mutation into osteoclasts resulted in an increased ITGB5 and reduced PRF1 expression of borderline significance. Finally, we observed that the ADO II patients presented a normal or increased serum level of bone formation markers, demonstrating a coupling between dysfunctional osteoclasts and osteoblasts. Sphingosine kinase 1 mRNA was expressed at the same level in ADO II and control osteoclasts. In conclusion, these data suggest that in addition to an acidification dysfunction caused by the CLCN7 mutation, a change in ITGB5, PRF1, WARS, and SERPINE2 expression could be part of the osteoclastic phenotype of ADO II. PMID:24336069
Coudert, Amélie E; Del Fattore, Andrea; Baulard, Céline; Olaso, Robert; Schiltz, Corinne; Collet, Corinne; Teti, Anna; de Vernejoul, Marie-Christine
Inhibition of neovascularization but not fibrosis with the fluocinolone acetonide implant in autosomal dominant neovascular inflammatory vitreoretinopathy.
OBJECTIVE To review the effect of the fluocinolone acetonide implant in subjects with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), an inherited autoimmune uveitis. METHODS A retrospective case series was assembled from patients with ADNIV who received fluocinolone acetonide implants. Visual acuity and features of ADNIV, including inflammatory cells, neovascularization, fibrosis, and cystoid macular edema, were reviewed. RESULTS Nine eyes of 5 related patients with ADNIV with uncontrolled inflammation were reviewed. Follow-up ranged from 21.7 to 56.7 months. Visual acuity at implantation ranged from 20/40 to hand motion. Preoperatively, 8 eyes had vitreous cells (a ninth had diffuse vitreous hemorrhage). Eight eyes had cystoid macular edema, 7 had an epiretinal membrane, and 3 had retinal neovascularization. Following implantation, vitreous cells resolved in all eyes and neovascularization regressed or failed to develop. Central macular thickness improved in 4 eyes. During the postoperative course, however, visual acuity continued to deteriorate, with visual acuity at the most recent examination ranging from 20/60 to no light perception. There was also progressive intraocular fibrosis and phthisis in 1 case. Four eyes underwent cataract surgery. Six of the 7 eyes without previous glaucoma surgery had elevated intraocular pressure at some point, and 3 of these required glaucoma surgery. CONCLUSIONS The fluocinolone acetonide implant may inhibit specific features of ADNIV such as inflammatory cells and neovascularization but does not stabilize long-term vision, retinal thickening, or fibrosis. All eyes in this series required cataract extraction, and more than half required surgical intervention for glaucoma. Further studies may identify additional therapies and any benefit of earlier implantation. PMID:22777573
Tlucek, Paul S; Folk, James C; Orien, Jason A; Stone, Edwin M; Mahajan, Vinit B
Novel three-dimensional imaging volumetry in autosomal dominant polycystic kidney disease: comparison with 2D volumetry.
Background: Autosomal dominant polycystic kidney disease (ADPKD) volumetry is an important marker for evaluating the progression of disease. Three-dimensional (3D) volumetry is generally more timesaving than 2D volumetry, but its reliability and accuracy are uncertain. Methods: Small and large phantoms simulating polycystic kidneys and 20 patients with ADPKD underwent magnetic resonance imaging (MRI) volumetry. We evaluated the total kidney volume (TKV) and total cyst volume (TCV) using a novel 3D volumetry program (XelisTM) and compared 3D volumetry data with the conventional 2D method (the reference volume values). After upload and threshold setting, the other organs surrounding the kidney were removed by picking and sculpting. The novel method involves drawing of the kidney or cyst and automatic measurement of kidney volume and cyst volume in 3D images. Results: The 3D volume estimation of the small and large phantoms differed from the actual values by 6.9% and -8.2%, respectively, for TKV and by 2.1% and 1.4% for TCV. In ADPKD patients, the intra-reader reliability of 3D volumetry was 30 ± 180 mL (1.3 ± 10.3%) and 25 ± 113 mL (1.2 ± 9.4%), respectively, for TKV and TCV. Correlation between 3D volumetry and 2D volumetry of TKV and TCV resulted in a high correlation coefficient and a regression slope approaching 1.00 (r = 0.97 - 0.98). The mean of the volume percentage differences for 3D vs. 2D for TKV : TCV were -6.0 ± 8.9% : 2.0 ± 11.8% in large ADPKD and -16.1 ± 10.4% : 13.2 ± 21.9% in small ADPKD. Conclusion: Our study showed that 3D volumetry has reliability and accuracy compared with 2D volumetry in ADPKD. 3D volumetry is more accurate for TCV and large ADPKD. PMID:25029513
Shin, Dongsuk; Lee, Kyu-Beck; Hyun, Young Youl; Lee, Young Rae; Hwang, Young-Hwan; Park, Hayne Cho; Ahn, Curie
Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in the genes for polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2). Typical onset is in middle age, with gradual replacement of renal tissue with thousands of fluid-filled cysts, resulting in end-stage renal disease requiring dialysis or kidney transplantation. There currently are no approved therapies to slow or cure ADPKD. Mutations in the PKD1 and PKD2 genes abnormally activate multiple signaling proteins and pathways regulating cell proliferation, many of which we observe, through network construction, to be regulated by heat shock protein 90 (HSP90). Inhibiting HSP90 with a small molecule, STA-2842, induces the degradation of many ADPKD-relevant HSP90 client proteins in Pkd1(-/-) primary kidney cells and in vivo. Using a conditional Cre-mediated mouse model to inactivate Pkd1 in vivo, we find that weekly administration of STA-2842 over 10 wk significantly reduces initial formation of renal cysts and kidney growth and slows the progression of these phenotypes in mice with preexisting cysts. These improved disease phenotypes are accompanied by improved indicators of kidney function and reduced expression and activity of HSP90 clients and their effectors, with the degree of inhibition correlating with cystic expansion in individual animals. Pharmacokinetic analysis indicates that HSP90 is overexpressed and HSP90 inhibitors are selectively retained in cystic versus normal kidney tissue, analogous to the situation observed in solid tumors. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD. PMID:23858461
Seeger-Nukpezah, Tamina; Proia, David A; Egleston, Brian L; Nikonova, Anna S; Kent, Tatiana; Cai, Kathy Q; Hensley, Harvey H; Ying, Weiwen; Chimmanamada, Dinesh; Serebriiskii, Ilya G; Golemis, Erica A
Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex
Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery.
Pasternack, Sandra M.; Refke, Melanie; Paknia, Elham; Hennies, Hans Christian; Franz, Thomas; Schafer, Niklas; Fryer, Alan; van Steensel, Maurice; Sweeney, Elizabeth; Just, Miquel; Grimm, Clemens; Kruse, Roland; Ferrandiz, Carlos; Nothen, Markus M.; Fischer, Utz; Betz, Regina C.
Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex.
Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery. PMID:23246290
Pasternack, Sandra M; Refke, Melanie; Paknia, Elham; Hennies, Hans Christian; Franz, Thomas; Schäfer, Niklas; Fryer, Alan; van Steensel, Maurice; Sweeney, Elizabeth; Just, Miquel; Grimm, Clemens; Kruse, Roland; Ferrándiz, Carlos; Nöthen, Markus M; Fischer, Utz; Betz, Regina C
Exon Sequencing of PKD1 Gene in an Iranian Patient with Autosomal-Dominant Polycystic Kidney Disease
Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with the incidence of 1 in 1,000 births. ADPKD is genetically heterogeneous with two genes identified: PKD1 (16p13.3, 46 exons) and PKD2 (4q21, 15 exons). Eighty five percent of the patients with ADPKD have at least one mutation in the PKD1 gene. Genetic studies have demonstrated an important allelic variability among patients, but very few data are known about the genetic variation among Iranian populations. Methods: In this study, exon direct sequencing of PKD1 was performed in a seven-year old boy with ADPKD and in his parents. The patient's father was ADPKD who was affected without any kidney dysfunction, and the patient's mother was congenitally missing one kidney. Results: Molecular genetic testing found a mutation in all three members of this family. It was a missense mutation GTG>ATG at position 3057 in exon 25 of PKD1. On the other hand, two novel missense mutations were reported just in the 7-year-old boy: ACA>GCA found in exon 15 at codon 2241 and CAC>AAC found in exon 38 at codon 3710. For checking the pathogenicity of these mutations, exons 15, 25, and 38 of 50 unrelated normal cases were sequenced. Conclusion: our findings suggested that GTG>ATG is a polymorphism with high frequency (60%) as well as ACA>GCA and CAC>AAC are polymorphisms with frequencies of 14% and 22%, respectively in the population of Southwest Iran.
Hafizi, Atousa; Khatami, Saeid Reza; Galehdari, Hamid; Shariati, Gholamreza; Saberi, Ali Hossein; Hamid, Mohammad
Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.
Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way. PMID:16437702
Peces, Ramón; Drenth, Joost P H; Te Morsche, Rene H M; González, Pedro; Peces, Carlos
Autosomal dominant familial spastic paraplegia: Reduction of the FSPI candidate region on chromosome 14q to 7 cM and locus heterogeneity
Three large pedigrees of Germany descent with autosomal dominant {open_quotes}pure{close_quotes} familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigree D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP. 11 refs., 2 figs., 2 tabs.
Gispert, S.; Santos, N.; Auburger, G.; Damen, R.; Voit, T. [University Hospital, Duesseldorf (Germany); Schulz, J.; Klockgether, T. [University Hospital, Tuebingen (Germany); Orozco, G. [Hospital Lenin, Holguin (Cuba); Kreuz, F. [Technical Univ., Dresden (Netherlands); Weissenbach, J. [Unite de Genetique, Paris (France)
Identification of a New Thyrotropin Receptor Germline Mutation (Leu629Phe) in a Family with Neonatal Onset of Autosomal Dominant Nonautoimmune Hyperthyroidism
Constitutively activating germline mutations in the TSH receptor (TSHR) gene have been identified as a cause of autosomal dominant nonautoimmune hyperthyroidism and sporadic congenital hyperthy- roidism. We report a 10-yr-old boy and his 31-yr-old mother, both presenting with a history of recurring toxic thyroid hyperplasia and no evidence for autoimmune thyroid disease. In the boy, onset of hyperthyroidism and goiter
Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2
Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder. At least two distinct forms of ADPKD are now well defined. In âĽ86% of affected European families, a gene defect localized to 16p13.3 was responsible for ADPKD, while a second locus has been recently localized to 4q13-q23 as candidate for the disease in the remaining families. We present confirmation
J. L. San Millan; M. Viribay; B. Peral; F. Moreno; I. Martinez; J. Weissenbach
Autosomal Dominant Hypocalcemia Caused by an Activating Mutation of the Calcium-Sensing Receptor Gene: The First Case Report in Korea
Hypoparathyroidism is an abnormality of calcium metabolism characterized by low serum levels of parathyroid hormone in spite of hypocalcemia. The causes of hypoparathyroidism are numerous. Activating mutations in the calcium-sensing receptor (CaSR) gene are well-known causes of familial isolated hypoparathyroidism, also known as autosomal dominant hypocalcemia (ADH). Here we describe members of a Korean family with a heterozygous Pro221Leu mutation causing ADH. This case is the first report in Korea.
Kim, Mi Yeon; Tan, Alice Hyun Kyung; Ki, Chang-Seok; Lee, Ji In; Jang, Hye Won; Shin, Hyun Won; Kim, Sun Wook; Min, Yong-Ki; Lee, Myung-Shik; Lee, Moon-Kyu; Kim, Kwang-Won
Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa
Autosomal dominant retinitis pigmentosa (adRP) is a heterogeneous set of progressive retinopathies caused by several distinct genes. One locus, the RP10 form of adRP, maps to human chromosome 7q31.1 and may account for 5–10% of adRP cases among Americans and Europeans. We identified two American families with the RP10 form of adRP by linkage mapping and used these families to reduce the linkage interval to 3.45 Mb between the flanking markers D7S686 and RP-STR8. Sequence and transcript analysis identified 54 independent genes within this region, at least 10 of which are retinal-expressed and thus candidates for the RP10 gene. A screen of retinal transcripts comparing retinas from normal mice to retinas from crx?/crx? knockout mice (with poorly differentiated photoreceptors) demonstrated a 6-fold reduction in one candidate, inosine monophosphate dehydrogenase 1 (IMPDH1; EC 22.214.171.124). Since many of the genes known to cause retinitis pigmentosa are under CRX control in photoreceptors, IMPDH1 became a high-priority candidate for mutation screening. DNA sequencing of affected individuals from the two American RP10 families revealed a GAC?AAC transition in codon 226 substituting an asparagine for an aspartic acid in both families. The identical mutation was also found in a British RP10 family. The Asp226Asn missense mutation is present in all affected individuals tested and absent from unaffected controls. The aspartic acid at codon 226 is conserved in all IMPDH genes, in all species examined, including bacteria, suggesting that this mutation is highly deleterious. Subsequent screening of probands from 60 other adRP families revealed an additional family with this mutation, confirming its association with retinitis pigmentosa and the relatively high frequency of this mutation. Another IMPDH1 substitution, Val268Ile, was also observed in this cohort of patients but not in controls. IMPDH1 is a ubiquitously expressed enzyme, functioning as a homotetramer, which catalyzed the rate-limiting step in de novo synthesis of guanine nucleotides. As such, it plays an important role in cyclic nucleoside metabolism within photoreceptors. Several classes of drugs are known to affect IMPDH isoezymes, including nucleotide and NAD analogs, suggesting that small-molecule therapy may be available, one day, for RP10 patients.
Bowne, Sara J.; Sullivan, Lori S.; Blanton, Susan H.; Cepko, Constance L.; Blackshaw, Seth; Birch, David G.; Hughbanks-Wheaton, Dianna; Heckenlively, John R.; Daiger, Stephen P.
Characteristics of Intracranial Aneurysms in the Else Kr?ner-Fresenius Registry of Autosomal Dominant Polycystic Kidney Disease
Background Patients who harbor intracranial aneurysms (IAs) run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD). Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. Methods We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Results Of 463 eligible ADPKD patients from the population base of Germany, 32 (7%) were found to have IAs, diagnosed at the age of 2–71 years, 19 females and 13 males. Twenty (63%) of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%), IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93%) had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14%) had MR angiography. Conclusion In ADPKD, rupture of IAs occurs frequently before the start of dialysis, is only infrequently associated with a family history of IAs or subarachnoid hemorrhage, and is associated with mutations either of the PKD1 or the PKD2 gene of any type. Screening for IAs is widely insufficiently performed, should not be restricted to families with a history of cerebral events and should be started before end-stage renal failure.
Neumann, Hartmut P.H.; Malinoc, Angelica; Bacher, Janina; Nabulsi, Zinaida; Ivanovas, Vera; Bruechle, Nadine Ortiz; Mader, Irina; Hoffmann, Michael M.; Riegler, Peter; Kraemer-Guth, Annette; Burchardi, Christian; Schaeffner, Elke; Martin, Rodolfo S.; Azurmendi, Pablo J.; Zerres, Klaus; Jilg, Cordula; Eng, Charis; Glasker, Sven
Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations.
We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilateral agenesis of the tibia, and club foot. The ultrasonographic picture was consistent with a diagnosis of polycystic kidney disease, either the adult onset autosomal dominant type (ADPKD) or the early onset autosomal recessive form (ARPKD). However, there was a positive family history for ADPKD. Linkage analysis was performed in 10 family members, of whom four were affected, using six flanking DNA markers tightly linked to the PKD1 locus on chromosome 16p, and one marker linked to the putative PKD2 locus on chromosome 2p. Lod score determinations indicated that the affected gene in the family is most likely PKD1. The patient inherited the disease linked haplotype from his affected mother. PMID:8320707
Turco, A E; Padovani, E M; Chiaffoni, G P; Peissel, B; Rossetti, S; Marcolongo, A; Gammaro, L; Maschio, G; Pignatti, P F
Autosomal Dominant Pseudohypoparathyroidism Type Ib: A Novel Inherited Deletion Ablating STX16 Causes Loss of Imprinting at the A/B DMR.
Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein ?-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods. Objective: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underlying primary genetic defect. Patient and Methods: A PHP-Ib patient (hypocalcaemia, hyperphosphataemia, raised serum PTH levels, no vitamin D deficiency) and his unaffected relatives were investigated by methylation specific-multiplex ligand-dependent probe amplification to search for novel pathogenetic defects affecting the guanine nucleotide-binding protein ?-stimulating activity polypeptide 1 and STX16 loci. Results: We report the clinical, biochemical, and molecular analysis of an AD-PHP-Ib patient with a novel STX16 deletion overlapping with previously identified STX16 deletions but that, unlike these genetic defects associated with AD-PHP-Ib, goes unnoticed with commonly used first-level diagnostic techniques. Conclusions: Our work highlights the importance of performing accurate investigations in PHP-Ib patients with methylation defects to allow precise genetic counseling because, in case of deletions, the segregation ratio is about 50% and the disease phenotype is transmitted in an autosomal dominant fashion via the mother. PMID:24438374
Elli, Francesca M; de Sanctis, Luisa; Peverelli, Erika; Bordogna, Paolo; Pivetta, Barbara; Miolo, Gianmaria; Beck-Peccoz, Paolo; Spada, Anna; Mantovani, Giovanna
Recurrent Mutation in the First Zinc Finger of the Orphan Nuclear Receptor NR2E3 Causes Autosomal Dominant Retinitis Pigmentosa
"Autosomal dominant retinitis pigmentosa" (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A heterozygous mutation c.166G?A (p.Gly56Arg) was identified in the first zinc finger of NR2E3 in a large Belgian family affected with adRP. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Interestingly, affected members of these families display a novel recognizable NR2E3-related clinical subtype of adRP. Other mutations of NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome, a specific retinal phenotype. We propose a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributed to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance.
Coppieters, Frauke; Leroy, Bart P.; Beysen, Diane; Hellemans, Jan; De Bosscher, Karolien; Haegeman, Guy; Robberecht, Kirsten; Wuyts, Wim; Coucke, Paul J.; De Baere, Elfride
Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred.
We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings. PMID:9714015
Ahmad, M; Faiyaz Ul Haque, M; Ahmad, W; Abbas, H; Haque, S; Krakow, D; Rimoin, D L; Lachman, R S; Cohn, D H
Chronic kidney pain in autosomal dominant polycystic kidney disease: a case report of successful treatment by catheter-based renal denervation.
Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter-based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old woman whose chronic pain could not be controlled by pain medication or splanchnic nerve blockade. Transluminal radiofrequency renal denervation was performed as an experimental therapeutic option with an excellent result, indicating that this procedure should be considered for chronic pain management in ADPKD. PMID:24518126
Casteleijn, Niek F; de Jager, Rosa L; Neeleman, M Peer; Blankestijn, Peter J; Gansevoort, Ron T
Icelandic families with autosomal dominant polycystic kidney disease: families unlinked to chromosome 16p13.3 revealed by linkage analysis
We have mainly used 3 highly polymorphic DNA markers, 3'HVR (D16S85), 16AC2.5 (D16S291) and SM7 (D16S283), flanking the PKD1 region on chromosome 16p13.3 to establish linkage status in seven Icelandic families with autosomal dominant polycystic kidney disease (ADPKD). In four families, the disease locus is in the PKD1 region, and three families are "unlinked" to chromosome 16p13.3. In one of
Ragnheiđur Fossdal; Magnus Böđarsson; Páll Ásmundsson; Jóhann Ragnarsson; Dorien Peters; Martijn H. Breuning; Ólafur Jensson
A novel locus ( CORD12 ) for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1
Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies\\u000a leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French\\u000a family with autosomal dominant (ad) CRD.\\u000a \\u000a \\u000a \\u000a \\u000a Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome\\u000a SNP analysis with the use
Gaël Manes; Maxime Hebrard; Béatrice Bocquet; Isabelle Meunier; Delphine Coustes-Chazalette; Audrey Sénéchal; Anne Bolland-Augé; Diana Zelenika; Christian P Hamel
Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus
The detailed clinical, electrophysiological and imaging data of three German autosomal dominant cerebellar ataxia (ADCA) families\\u000a are reported. Linkage to SCA2 was established using microsatellite markers D12S105, D12S1339(1328), D12S 1340(1329) yielding\\u000a a lod score exceeding +3.0 for the combined data. Analysis of the pedigree data provided evidence of anticipation as observed\\u000a in other neurodegenerative disorders due to polyglutamine expansion encoded
K. Bürk; G. Stevanin; O. Didierjean; G. Cancel; Y. Trottier; M. Skalej; M. Abele; A. Brice; J. Dichgans; T. Klockgether
Combined Liver and Kidney Transplant in a Patient with Budd-Chiari Syndrome Secondary to Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease: Report of a Case with a 9-Year Follow-Up
Polycystic liver disease (PLD) is a hereditary disease inherited by autosomal dominant trait that occurs as a frequent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). We report a case of a 59-year-old woman diagnosed with ADPKD associated with PLD. End-stage chronic renal failure with a secondary Budd-Chiari syndrome developed during the patient's clinical course. She underwent combined liver and kidney transplantation, with a successful response over a 9-year follow-up period.
Ramirez de la Piscina, Patricia; Duca, Ileana; Estrada, Silvia; Calderon, Rosario; Ganchegui, Idoia; Campos, Amaia; Spicakova, Katerina; Salvador, Marta; Delgado, Elvira; Bengoa, Raquel; Garcia-Campos, Francisco
The PROM1 Mutation p.R373C Causes an Autosomal Dominant Bull's Eye Maculopathy Associated with Rod, Rod-Cone, and Macular Dystrophy
Purpose. To characterize in detail the phenotype of five unrelated families with autosomal dominant bull's eye maculopathy (BEM) due to the R373C mutation in the PROM1 gene. Methods. Forty-one individuals of five families of Caribbean (family A), British (families B, D, E), and Italian (family C) origin, segregating the R373C mutation in PROM1, were ascertained. Electrophysiological assessment, fundus autofluorescence (FAF) imaging, fundus fluorescein angiography (FFA), and optical coherence tomography (OCT) were performed in available subjects. Mutation screening of PROM1 was performed. Results. The R373C mutant was present heterozygously in all affected patients. The age at onset was variable and ranged between 9 and 58 years, with most of the individuals presenting with reading difficulties. Subjects commonly had a mild to moderate reduction in visual acuity except for members of family C who experienced markedly reduced central vision. The retinal phenotype was characterized by macular dystrophy, with retinal pigment epithelial mottling in younger subjects, progressing to typical BEM over time, with the development of macular atrophy in older patients. In addition, all members of family C had typical features of RP. The electrophysiological findings were variable both within and between families. Conclusions. Mutations in PROM1 have been described to cause a severe form of autosomal recessive RP in two families of Indian and Pakistani descent. The results of this study have demonstrated that a distinct redundant PROM1 mutation (R373C) can also produce an autosomal dominant, fully penetrant retinopathy, characterized by BEM with little inter- and intrafamilial variability, and retinal dystrophy with variable rod or rod–cone dysfunction and marked intra- and interfamilial variability, ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod–cone dysfunction.
Michaelides, Michel; Gaillard, Marie-Claire; Escher, Pascal; Tiab, Leila; Bedell, Matthew; Borruat, Francois-Xavier; Barthelmes, Daniel; Carmona, Ruben; Zhang, Kang; White, Edward; McClements, Michelle; Robson, Anthony G.; Holder, Graham E.; Bradshaw, Keith; Hunt, David M.; Webster, Andrew R.; Moore, Anthony T.; Schorderet, Daniel F.; Munier, Francis L.
Clinical and molecular analysis of a Chinese family with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel missense mutation in the vasopressin-neurophysin II gene.
The objective of this study is to identify the genetic defects in a Chinese family with autosomal dominant familial neurohypophyseal diabetes insipidus. Complete physical examination, fluid deprivation, and DDAVP tests were performed in three affected and three healthy members of the family. Genomic DNA was extracted from leukocytes of venous blood of these individuals for polymerase chain reaction amplification and direct sequencing of all three coding exons of arginine vasopressin-neurophysin II (AVP-NPII) gene. Seven members of this family were suspected to have symptomatic vasopressin-deficient diabetes insipidus. The water deprivation test in all the patients confirmed the diagnosis of vasopressin-deficient diabetes insipidus, with the pedigree demonstrating an autosomal dominant inheritance. Direct sequence analysis revealed a novel mutation (c.193T>A) and a synonymous mutation (c.192C>A) in the AVP-NPII gene. The missense mutation resulted in the substitution of cysteine by serine at a highly conserved codon 65 of exon 2 of the AVP-NPII gene in all affected individuals, but not in unaffected members. We concluded that a novel missense mutation in the AVP-NPII gene caused neurohypophyseal diabetes insipidus in this family, due to impaired neurophysin function as a carrier protein for AVP. The Cys65 is essential for NPII in the formation of a salt bridge with AVP. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the normal expression of vasopressin. PMID:22307687
Luo, Yongfeng; Wang, Binbin; Qiu, Yu; Zhang, Chuan; Jin, Chengluo; Zhao, Yakun; Zhu, Qingguo; Ma, Xu
Clinical and muscle magnetic resonance imaging study of an Italian family with autosomal dominant inclusion body myopathy not linked to known genetic loci.
The objective was to report a clinical, pathological and muscle magnetic resonance (MR) study of an Italian family with an autosomal dominant inclusion body myopathy (AD-IBM). Eight subjects (age range 20-56 years; 5 females and 3 males) belonging to four generations were studied. Onset of disturbances (distal weakness at lower limbs) ranged from 20 to 28 years. CK levels were increased to five times. Only in an early stage oedema of involved muscles has been demonstrated by muscle MR. Quadriceps femoris was characteristically spared; in the last phases a mild involvement of the vasti became evident with persistent sparing of the rectus femori. Rimmed vacuoles and hyperphosphorylated tau filaments were evident at muscle biopsy. Linkage analysis excluded the association of the disease to chromosome loci 14q11, 17p13.1, 2p13, 19p13. The study suggests that quadriceps sparing is a characteristic feature also of AD-IBM. This finding could represent a muscle-image hallmark helpful in diagnosis of autosomal dominant muscular disorders. PMID:16388363
Rodolico, C; Toscano, A; Patitucci, A; Muglia, M; Gaeta, M; D'Arrigo, G; Migliorato, A; Messina, S; Quattrone, A; Messina, C; Vita, G
The Polymorphism of the ACE Gene Affects Left Ventricular Hypertrophy and Causes Disturbances in Left Ventricular Systolic/Diastolic Function in Patients with Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequently occurring autosomal diseases inherited in the dominant manner. Due to this, lesions in the cardiovascular system of ADPKD patients have caught the attention of clinical investigators worldwide. The aim of the study was to analyse cardiovascular complications in ADPKD patients with a focus on left ventricular hypertrophy (LVH) and selected components of its systolic/diastolic function based on echocardiography. The study was conducted on 55 patients with ADPKD (24 males, 31 females), subdivided into three groups according to the stage of chronic kidney disease (CKD). The patient group with ADPKD and ESRD (group C) manifested an increased incidence of the D allele as compared to group A and group B (?2 = 4.217, P = 0.04). In all ADPKD patients with the DD genotype, left ventricular mass (LVM), posterior wall thickness (PWT), and interventricular septal thickness (IVS) were significantly higher compared to patients possessing the II and ID genotypes (P < 0.02, P < 0.003, and P < 0.009, resp.). The DD genotype exists more frequently in ADPKD patients with ESRD and is associated with a higher occurrence of LVH and disturbances in systolic-diastolic function when compared to ADPKD ESRD patients with the II and ID genotypes.
Wanic-Kossowska, Maria; Kobelski, Mikolaj; Pawliczak, Elzbieta; Hoppe, Krzysztof; Sikorska, Dorota
Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study
Background Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD). Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus) markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT) to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD. Method/design This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune®) in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI) volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus. Discussion The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD. Trial registration NCT00346918
Serra, Andreas L; Kistler, Andreas D; Poster, Diane; Struker, Marian; Wuthrich, Rudolf P; Weishaupt, Dominik; Tschirch, Frank
Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree
BACKGROUND/AIMS—Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR.?METHODS—Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13.?RESULTS—The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q.?CONCLUSION—This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.??
Bamashmus, M; Downey, L; Inglehearn, C; Gupta, S; Mansfield, D
A Complex Phenotype of Peripheral Neuropathy, Myopathy, Hoarseness and Hearing Loss is Linked to an Autosomal Dominant Mutation in MYH14
Both peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. A complex phenotype of peripheral neuropathy, myopathy, hoarseness and hearing loss was diagnosed in a large autosomal dominant Korean family. A high density SNP-based linkage study mapped the underlying gene to a region on chromosome 19q13.3. The maximum multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel c.2822G>T (p.Arg941Leu) mutation in the gene MYH14, which encodes the nonmuscle myosin heavy chain 14. Clinically we observed a sequential pattern of the onset of muscle weakness starting from the anterior to the posterior leg muscle compartments followed by involvement of intrinsic hand and proximal muscles. The hearing loss and hoarseness followed the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic features in the affected patients. While mutations in MYH14 have been shown to cause nonsyndromic autosomal dominant hearing loss (DFNA4), the peripheral neuropathy, myopathy, and hoarseness have not been associated with MYH14. Therefore, we suggest that the identified mutation in MYH14 significantly expands the phenotypic spectrum of this gene.
Choi, Byung-Ok; Kang, Sung Hee; Hyun, Young Se; Kanwal, Sumaria; Park, Sun Wha; Koo, Heasoo; Kim, Sang-Beom; Choi, Young-Chul; Yoo, Jeong Hyun; Kim, Jong-Won; Park, Kee Duk; Choi, Kyoung-Gyu; Kim, Song Ja; Zuchner, Stephan; Chung, Ki Wha
Brachydactyly E: isolated or as a feature of a syndrome
Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals.
Genetic Linkage of Autosomal-Dominant Alport Syndrome with Leukocyte Inclusions and Macrothrombocytopenia (Fechtner Syndrome) to Chromosome 22q11-13
Summary Fechtner syndrome is an autosomal-dominant variant of Alport syndrome, manifested by nephritis, sensorineural hearing loss, cataract formation, macrothrombocytopenia, and polymorphonuclear inclusion bodies. As opposed to autosomal-recessive and X-linked Alport syndromes, which have been genetically well studied, the genetic basis of Fechtner syndrome remains elusive. We have mapped the disease-causing gene to the long arm of chromosome 22 in an extended Israeli family with Fechtner syndrome plus impaired liver functions and hypercholesterolemia in some individuals. Six markers from chromosome 22q yielded a LOD score >3.00. A maximum two-point LOD score of 7.02 was obtained with the marker D22S283 at a recombination fraction of 0. Recombination analysis placed the disease-causing gene in a 5.5-Mb interval between the markers D22S284 and D22S1167. No collagen genes or genes comprising the basement membrane have been mapped to this region.
Toren, Amos; Amariglio, Ninette; Rozenfeld-Granot, Galit; Simon, Amos J.; Brok-Simoni, Frida; Pras, Elon; Rechavi, Gideon
Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production. PMID:7732783
Schröder, J M; Sellhaus, B; Jörg, J
Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disorder of the cerebral small blood vessels caused by a mutation in the NOTCH3 gene, which encodes a large transmembrane receptor NOTCH3. It is associated with systemic arteriopathy involving small arteries, besides the brain, in skin, spleen, liver, muscle, aorta and in the kidney. The key pathological finding is the accumulation of granular osmiophilic material (GOM) on degenerating vascular smooth muscle cells. In the kidney GOMs have been described only in a very limited number of CADASIL patients. We describe a genetically confirmed CADASIL patient with mild renal dysfunction and GOMs in the interlobular and juxtaglomerular arteries and, for the first time, also within the glomerulus, whose nephrology conditions remained stable, whereas the neurological manifestations markedly worsened over a six-year follow-up period. The reasons for this discrepancy are probably related to differences in the structure and function of brain and kidney blood vessels. PMID:22936449
Ragno, Michele; Trojano, Luigi; Pianese, Luigi; Boni, Maria Virginia; Silvestri, Serena; Mambelli, Vladimiro; Lorenzi, Teresa; Scarpelli, Marina; Morroni, Manrico
Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number-Variable Region at Chromosome 4p16
Recently, large-scale benign copy-number variations (CNVs)—encompassing over 12% of the genome and containing genes considered to be dosage tolerant for human development—were uncovered in the human population. Here we present a family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct. This phenotype is linked to a cytogenetically visible alteration at 4pter consisting of five copies of a copy-number-variable region, encompassing a low-copy repeat (LCR)-rich sequence. We demonstrate that the ?750 kb amplicon occurs in exact tandem copies. This is the first example of an amplified CNV associated with a Mendelian disorder, a discovery that implies that genome screens for genetic disorders should include the analysis of so-called benign CNVs and LCRs.
Balikova, Irina; Martens, Kevin; Melotte, Cindy; Amyere, Mustapha; Van Vooren, Steven; Moreau, Yves; Vetrie, David; Fiegler, Heike; Carter, Nigel P.; Liehr, Thomas; Vikkula, Miikka; Matthijs, Gert; Fryns, Jean-Pierre; Casteels, Ingele; Devriendt, Koen; Vermeesch, Joris Robert
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Z{sub max} = 37.24 at {theta} = .01) was obtained with marker D19S841, a new CA{sub n} microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region. 35 refs., 5 figs., 2 tabs.
Ducros, A.; Alamowitch, S.; Nagy, T. [INSERM U25, Paris (France)] [and others
Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome
Background Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with "genotype-negative/phenotype-positive" LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II–III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2's PEST domain. Conclusions This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.
Boczek, Nicole J.; Best, Jabe M.; Tester, David J.; Giudicessi, John R.; Middha, Sumit; Evans, Jared M.; Kamp, Timothy J.; Ackerman, Michael J.
Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3.
A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients. PMID:23538131
van Beelen, E; Schraders, M; Huygen, P L M; Oostrik, J; Plantinga, R F; van Drunen, W; Collin, R W J; Kooper, D P; Pennings, R J E; Cremers, C W R J; Kremer, H; Kunst, H P M
Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred
Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.
Andermann, F.; Andermann, E.; Carpenter, S. [and others
Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.
Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438. PMID:16698014
Dadgar, Sharareh; Hagens, Olivier; Dadgar, Seyed Razi; Haghighi, Ehsan Nobakht; Schimpf, Simone; Wissinger, Bernd; Garshasbi, Masoud
Benign adult familial myoclonus epilepsy (BAFME): an autosomal dominant form not linked to the dentatorubral pallidoluysian atrophy (DRPLA) gene.
The genetic differences between two types of dominant inherited myoclonus epilepsy, dentatorubral pallidoluysian atrophy (DRPLA) and benign adult familial myoclonus epilepsy (BAFME), have been reported. A gene with a CAG repeat expansion responsible for DRPLA has been isolated. We have examined CAG repeat expansion in the DRPLA gene in five BAFME families, and the abnormal CAG expansion was not observed in the affected subjects. Linkage analysis using DNA polymorphisms in the DRPLA gene and the genes for gamma-aminobutyric acid (GABA) receptor subunits, GABAR beta 1, GABAR beta 3, and GABAR alpha 6, showed that these genes were not responsible for BAFME. Images
Kuwano, A; Takakubo, F; Morimoto, Y; Uyama, E; Uchino, M; Ando, M; Yasuda, T; Terao, A; Hayama, T; Kobayashi, R; Kondo, I
Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.
Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype. PMID:22095935
Huijgen, Roeland; Sjouke, Barbara; Vis, Kelly; de Randamie, Janine S E; Defesche, Joep C; Kastelein, John J P; Hovingh, G Kees; Fouchier, Sigrid W
Recovery of Dominant, Autosomal Flightless Mutants of Drosophila Melanogaster and Identification of a New Gene Required for Normal Muscle Structure and Function
To identify further mutations affecting muscle function and development in Drosophila melanogaster we recovered 22 autosomal dominant flightless mutations. From these we have isolated eight viable and lethal alleles of the muscle myosin heavy chain gene, and seven viable alleles of the indirect flight muscle (IFM)-specific Act88F actin gene. The Mhc mutations display a variety of phenotypic effects, ranging from reductions in myosin heavy chain content in the indirect flight muscles only, to reductions in the levels of this protein in other muscles. The Act88F mutations range from those which produce no stable actin and have severely abnormal myofibrillar structure, to those which accumulate apparently normal levels of actin in the flight muscles but which still have abnormal myofibrils and fly very poorly. We also recovered two recessive flightless mutants on the third chromosome. The remaining five dominant flightless mutations are all lethal alleles of a gene named lethal(3)Laker. The Laker alleles have been characterized and the gene located in polytene bands 62A10,B1-62B2,4. Laker is a previously unidentified locus which is haplo-insufficient for flight. In addition, adult wild-type heterozygotes and the lethal larval trans-heterozygotes show abnormalities of muscle structure indicating that the Laker gene product is an important component of muscle.
Cripps, R. M.; Ball, E.; Stark, M.; Lawn, A.; Sparrow, J. C.
U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21
Background We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer's disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders. Findings We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF). Conclusions These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant ?-amyloid processing may influence U1 snRNP aggregate formation.
A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family.
Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear. PMID:24827932
Zhao, Yali; Wang, Dayong; Zong, Liang; Zhao, Feifan; Guan, Liping; Zhang, Peng; Shi, Wei; Lan, Lan; Wang, Hongyang; Li, Qian; Han, Bing; Yang, Ling; Jin, Xin; Wang, Jian; Wang, Jun; Wang, Qiuju
A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg2+ levels, with a prominent function for the Mg2+-transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane. Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K+) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K+ channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+ reabsorption.
Glaudemans, Bob; van der Wijst, Jenny; Scola, Rosana H.; Lorenzoni, Paulo J.; Heister, Angelien; van der Kemp, AnneMiete W.; Knoers, Nine V.; Hoenderop, Joost G.; Bindels, Rene J.
OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.
Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. PMID:11017080
Alexander, C; Votruba, M; Pesch, U E; Thiselton, D L; Mayer, S; Moore, A; Rodriguez, M; Kellner, U; Leo-Kottler, B; Auburger, G; Bhattacharya, S S; Wissinger, B
A Novel DFNA36 Mutation in TMC1 Orthologous to the Beethoven (Bth) Mouse Associated with Autosomal Dominant Hearing Loss in a Chinese Family
Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.
Zhao, Yali; Wang, Dayong; Zong, Liang; Zhao, Feifan; Guan, Liping; Zhang, Peng; Shi, Wei; Lan, Lan; Wang, Hongyang; Li, Qian; Han, Bing; Yang, Ling; Jin, Xin; Wang, Jian; Wang, Jun; Wang, Qiuju
Autosomal Recessive Transmission of a Rare KRT74 Variant Causes Hair and Nail Ectodermal Dysplasia: Allelism with Dominant Woolly Hair/Hypotrichosis
Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.
Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas
Autosomal Recessive Transmission of a Rare KRT74 Variant Causes Hair and Nail Ectodermal Dysplasia: Allelism with Dominant Woolly Hair/Hypotrichosis.
Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH. PMID:24714551
Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas
Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.
Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome. PMID:20691407
Williams, Stephen R; Aldred, Micheala A; Der Kaloustian, Vazken M; Halal, Fahed; Gowans, Gordon; McLeod, D Ross; Zondag, Sara; Toriello, Helga V; Magenis, R Ellen; Elsea, Sarah H
Haploinsufficiency of HDAC4 Causes Brachydactyly Mental Retardation Syndrome, with Brachydactyly Type E, Developmental Delays, and Behavioral Problems
Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4?/? mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.
Williams, Stephen R.; Aldred, Micheala A.; Der Kaloustian, Vazken M.; Halal, Fahed; Gowans, Gordon; McLeod, D. Ross; Zondag, Sara; Toriello, Helga V.; Magenis, R. Ellen; Elsea, Sarah H.
Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure.
Proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. Mutations in the PCSK9 gene have previously been found to segregate with autosomal dominant familial hypercholesterolemia (ADFH). In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed for two patients with a clinical diagnosis of familial hypercholesterolemia where mutation in the LDL-receptor gene hasn't been excluded. One missense mutation was detected in the exon 9 PCSK9 gene in the two ADFH patients. The patients were found to be heterozygote for Ile474Val (SNP rs562556). Using an array of in silico tools, we have investigated the effect of the above mutation on different structural levels of the PCSK9 protein. Although, the mutation has already been reported in the literature for other populations, to the best of our knowledge this is the first report of a mutation in the PCSK9 gene from the Arab population, including the Omani population. PMID:23386946
Al-Waili, Khalid; Al-Zidi, Ward Al-Muna; Al-Abri, Abdul Rahim; Al-Rasadi, Khalid; Al-Sabti, Hilal Ali; Shah, Karna; Al-Futaisi, Abdullah; Al-Zakwani, Ibrahim; Banerjee, Yajnavalka
Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations*?
Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1–10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cis-retinal chromophore during rod outer segment development.
Sakami, Sanae; Maeda, Tadao; Bereta, Grzegorz; Okano, Kiichiro; Golczak, Marcin; Sumaroka, Alexander; Roman, Alejandro J.; Cideciyan, Artur V.; Jacobson, Samuel G.; Palczewski, Krzysztof
Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21. 3-q. 22. 1
Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locus (gene SHFD1) maps to 7q21-q22. To characterize the SHFD1 locus, somatic cell hybrid lines were constructed from cytogenetically abnormal individuals with SHFD. Molecular analysis resulted in the localization of 93 DNA markers to one of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in four SHFD patients were encompassed by the smallest region of overlap among the SHFD-associated deletions. The order of DNA markers in the SHFD1 critical region has been defined as PON-D7S812-SHFD1-D7S811-ASNS. One DNA marker, D7S811, detected altered restriction enzyme fragments in three patients with translocations when examined by pulsed-field gel electrophoresis (PFGE). These data map SHFD1, a gene that is crucial for human limb differentiation, to a small interval in the q21.3-q.22.1 region of human chromosome 7. 54 refs., 4 figs., 2 tabs.
Scherer, S.W.; Tsui, L.C. (Univ. of Toronto (Canada)); Allen, T.; Kim, J.; Soder, S. (Hospital for Sick Children, Toronto (Canada)); Poorkaj, P.; Geshuri, D.; Nunes, M.; Stephens, K.; Pagon, R.A. (Univ. of Washington, Seattle, WA (United States)) (and others)
A third locus for autosomal dominant cerebellar ataxia Type I maps to chromosome 14q24. 3-qter: Evidence for the existence of a fourth locus
The autosomal dominant cerebellar ataxias (ADCA) type I are a group of neurological disorders that are clinically and genetically heterogeneous. Two genes implicated in the disease, SCA1 (spinal cerebellar ataxia 1) and SCA2, are already localized. The authors have mapped a third locus to chromosome 14q24.3-qter, by linkage analysis in a non-SCA1/non-SCA2 family and have confirmed its existence in a second such family. The authors suggest designating this new locus [open quotes]SCA3.[close quotes] Combined analysis of the two families restricted the SCA3 locus to a 15-cM interval between markers D14S67 and D14S81. The gene for Machado-Joseph disease (MJD), a clinically different form of ADCA type I, has been recently assigned to chromosome 14q24.3-q32. Although the SCA3 locus is within the MJD region, linkage analyses cannot yet demonstrate whether they result from mutations of the same gene. Linkage to all three loci (SCA1, SCA2, and SCA3) was excluded in another family, which indicates the existence of a fourth ADCA type I locus. 36 refs., 4 figs., 3 tabs.
Stevanin, G.; Guern, E.L.; Ravise, N.; Chneiweiss, H.; Duerr, A.; Cancel, G.; Vignal, A.; Boch, A.L.; Ruberg, M.; Penet, C.; Pothin, Y.; Lagroua, I.; Haguenau, M.; Rancurel, G.; Weissenbach, J.; Agid, Y.; Brice, A.
A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain.
Mutations in COCH have been associated with autosomal dominant nonsyndromic hearing loss (DFNA9) and are frequently accompanied by vestibular hypofunction. Here, we report identification of a novel missense mutation, p.F527C, located in the vWFA2 domain in members of a Korean family with late-onset and progressive hearing loss. To assess the molecular characteristics of this cochlin mutant, we constructed both wild-type and mutant cochlin constructs and transfected these into mammalian cell lines. Results of immunocytochemistry analysis demonstrated localization of the cochlin mutant in the endoplasmic reticulum/Golgi complex, whereas western blot analyses of cell lysates revealed that the mutant cochlin tends to form covalent complexes that are retained in the cell. Biochemical analyses of recombinant vWFA2 domain of cochlin carrying the p.F527C mutation revealed that the mutation increases propensity of the protein to form covalent disulfide-bonded dimers and affects the structural stability but not the collagen-affinity of the vWFA2 domain. We suggest that the instability of mutant cochlin is the major driving force for cochlin aggregation in the inner ear in DFNA9 patients carrying the COCH p.F527C mutation. PMID:22610276
Cho, Hyun-Ju; Park, Hong-Joon; Trexler, Maria; Venselaar, Hanka; Lee, Kyu-Yup; Robertson, Nahid G; Baek, Jeong-In; Kang, Beom Sik; Morton, Cynthia C; Vriend, Gert; Patthy, László; Kim, Un-Kyung
A Pkd1-Fbn1 genetic interaction implicates TGF-? signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-? binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-? signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-? signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-?. Our data link the interaction of two important diseases to a fundamental signaling pathway. PMID:24071006
Liu, Dongyan; Wang, Connie J; Judge, Daniel P; Halushka, Marc K; Ni, Jie; Habashi, Jennifer P; Moslehi, Javid; Bedja, Djahida; Gabrielson, Kathleen L; Xu, Hangxue; Qian, Feng; Huso, David; Dietz, Harry C; Germino, Gregory G; Watnick, Terry
APC-like congenital hypertrophy of the retinal pigment epithelium (CHRPE) in non-APC patients: Evidence for autosomal dominant transmission in one family
The presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE) is known to be the earliest phenotypic marker in carriers of a mutant allele of the adenomatous polyposis coli gene (APC). The specificity of CHRPE is known to be over 97%, provided that the lesions are bilateral and their total number higher than 4. In the present study, we describe 3 patients from 2 unrelated families with bilateral multiple asymptomatic CHRPE (8-17), normal visual function and no family history of APC. Clinical examination failed to detect other extracolonic signs of APC nor did a search for adenomatous polyps by colonscopy. In one family, the ocular phenotype was transmitted from a father to his only son. Mutation hot spots at codons 302, 622, 625, 1061 and 1309 of the APC gene (about 25% of germline mutations) were all tested normal. We postulate that these APC-free ocular findings reflect the allelic involvement of a mutant APC allele that remains to be characterized. However, involvement of another yet unrecognized autosomal dominant gene cannot be ruled out and additional families with this unique trait should be studied.
Thonney, E.; Munier, F.L. Pescia, G. [Universite de Lausanne (Switzerland)] [and others
HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31.
We report on a novel autosomal dominant disorder with variable phenotypic expression in a three-generation family; the major features include hypertelorism, preauricular sinus, deafness, and punctal pits with lacrimal-duct obstruction. We ruled out the involvement of EYA1, SIX1, and SIX5 as candidate genes by direct sequencing of their exons and by SNP-based linkage analysis. Subsequent SNP-based whole-genome genotyping and parametric multipoint linkage analysis gave lod scores >1 at 14q31 (LOD?=?3.14), 11q25 (LOD?=?1.87), and 8p23 (LOD?=?1.18). By genotyping additional microsatellite markers at two of these three loci and using an expanded phenotype definition, the LOD at 14q31 increased to 3.34. Direct sequencing of the gene exons within the 14q31 critical interval and a custom aCGH experiment did not show any pathogenic mutation or copy-number changes. Further sequencing of 21?kb of promoter regions showed a novel polymorphism 1,249?bp upstream from the SELIL start codon that segregated with the disease haplotype. Cloning the novel polymorphism into luciferase reporter constructs resulted in a 20% reduction in the expression levels. The identification of this family with a distinctive clinical phenotype and linkage to a novel locus at 14q31 supports the existence of a new syndrome of the branchial cleft. PMID:21480481
Sampath, Srirangan; Keats, Bronya J B; Lacassie, Yves
Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter. PMID:15605982
Miao, Qing; Paloneva, Timo; Tuominen, Susanna; Pöyhönen, Minna; Tuisku, Seppo; Viitanen, Matti; Kalimo, Hannu
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaloapthy (CADASIL): a hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic strokes starting in the third or fourth decade as a result of mutations in the Notch3 gene. Granular osmiophilic material (GOM) deposition around the vascular smooth muscle cells is a specific feature and electron microscopic observations of skin biopsies are useful for this diagnosis. A 39-year-old female with dizziness, abnormal visual fields, and hemiplegia, and a 42-year-old male with tinnitus and dizziness, were suspected of suffering from CADASIL based on MRI findings. Both cases were shown to have characteristic deposits of GOM, 200 to 800 nm in diameter, around the vascular smooth muscle cells of small arteries in the deep dermis, and thus the diagnoses of CADASIL were made, although there was no family history of cerebrovascular disorders or dementia. Dermatologists should be aware of these ultra-structural findings because this disease may occur sporadically and might be more common than initially thought. PMID:15798438
Ishiko, Akira; Shimizu, Atsushi; Nagata, Eiichiro; Ohta, Kouichi; Tanaka, Masaru
Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease
Background A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. Methods/design This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, ?1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. Discussion We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. Trial registration number Clinical trials.gov NCT01354405
Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure
Proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. Mutations in the PCSK9 gene have previously been found to segregate with autosomal dominant familial hypercholesterolemia (ADFH). In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed for two patients with a clinical diagnosis of familial hypercholesterolemia where mutation in the LDL-receptor gene hasn't been excluded. One missense mutation was detected in the exon 9 PCSK9 gene in the two ADFH patients. The patients were found to be heterozygote for Ile474Val (SNP rs562556). Using an array of in silico tools, we have investigated the effect of the above mutation on different structural levels of the PCSK9 protein. Although, the mutation has already been reported in the literature for other populations, to the best of our knowledge this is the first report of a mutation in the PCSK9 gene from the Arab population, including the Omani population.
Al-Waili, Khalid; Al-Zidi, Ward Al-Muna; Al-Abri, Abdul Rahim; Al-Rasadi, Khalid; Al-Sabti, Hilal Ali; Shah, Karna; Al-Futaisi, Abdullah; Al-Zakwani, Ibrahim; Banerjee, Yajnavalka
Genotype-phenotype correlation for DFNA22: characterization of non-syndromic, autosomal dominant, progressive sensorineural hearing loss due to MYO6 mutations.
Clinical and audiological examination was done in 2 Belgian families with autosomal dominant sensorineural hearing loss (SNHL) linked to DFNA22. Nineteen subjects in family 1 had mild to moderate SNHL starting in the third decade. The hearing loss was characterized by a flat audiogram affecting all tested frequencies with statistically significant progression. In family 2 eleven subjects were affected with mild to moderate SNHL starting in the second decade. Most of them showed a flat audiogram, but some had mid-frequency hearing loss. Significant progression of thresholds was present at 4 and 8 kHz. For all hitherto known DFNA22 families the audiological and clinical characteristics were correlated with the molecular data. This study describes the phenotype of 2 Belgian families with SNHL linked to DFNA22, both with a pathogenic change in the deafness gene MYO6. The phenotypes of all hitherto reported DFNA22 families with mutations in the MYO6 gene have been studied and compared. It seems that genetic defects that spare the motor domain of the myosin VI protein have a milder phenotype. PMID:19893302
Topsakal, Vedat; Hilgert, Nele; van Dinther, Joost; Tranebjaerg, Lisbeth; Rendtorff, Nanna D; Zarowski, Andrzej; Offeciers, Erwin; Van Camp, Guy; van de Heyning, Paul
A clinical, genetic, neuropathological study in a Japanese family with SCA 6 and a review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy.
This report concerns a Japanese family with genetically confirmed SCA 6, including an autopsy case, and a review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy (ADCCA). The proband (Case 1) was a Japanese woman. She developed gait disturbance at age 62. The father and younger sister (Case 2) had the same disorder. She died at age 67 due to subarachnoid hemorrhage. Neuropathological examination revealed severe loss of Purkinje cells in the cerebellum, prominently in the dorsal vermis, and absence of neuronal loss in the inferior olives. Molecular genetic study showed the CAG-repeat expansion of SCA 6 gene. The younger sister (Case 2) developed gait disturbance at age 62. Neurological examination at age 66 revealed cerebellar signs without sensory disturbance. Neuroimaging at this time showed cerebellar atrophy, prominently in the vermis. She died of multiple myeloma at age 66. A neuropathological review of Japanese autopsy cases of ADCCA showed that there are two patterns in the distribution of cerebellar cortical lesions of Japanese patients with ADCCA. The distribution of cerebellar cortical lesions in genetically confirmed Japanese patients with SCA 6 is more prominent in the vermis than in the hemisphere. PMID:9804117
Tsuchiya, K; Ishikawa, K; Watabiki, S; Tone, O; Taki, K; Haga, C; Takashima, M; Ito, U; Okeda, R; Mizusawa, H; Ikeda, K
A Missense Mutation in the Alpha-Actinin 1 Gene (ACTN1) Is the Cause of Autosomal Dominant Macrothrombocytopenia in a Large French Family
Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.
Gueguen, Paul; Rouault, Karen; Chen, Jian-Min; Raguenes, Odile; Fichou, Yann; Hardy, Elisabeth; Gobin, Eric; Pan-petesch, Brigitte; Kerbiriou, Mathieu; Trouve, Pascal; Marcorelles, Pascale; Abgrall, Jean-francois; Le Marechal, Cedric; Ferec, Claude
Hyperactive behavior in a family with autosomal dominant lateral temporal lobe epilepsy caused by a mutation in the LGI1/epitempin gene.
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. Attention-deficit/hyperactivity disorder (ADHD) symptoms have not yet been reported in these families. Clinical data were collected from a family with five affected members. Leucine-rich glioma-inactivated 1 exons and boundaries were sequenced by standard methods. Attention-deficit/hyperactivity disorder symptoms were scored based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Affected members had seizures with auditory features and psychic auras, and some experienced nightmares. A heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. This study expands the phenotypic spectrum associated with ADLTE due to LGI1 mutation and underlines the need for more systematic evaluation of ADHD and related symptoms. PMID:23651915
Berghuis, B; Brilstra, E H; Lindhout, D; Baulac, S; de Haan, G J; van Kempen, M
Role of Renin-Angiotensin-Aldosterone System Gene Polymorphisms andHypertension-induced End-stage RenalDisease in Autosomal Dominant Polycystic Kidney Disease.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidneys and is marked by progressive cyst growth and decline in kidney function, resulting in end-stage renal disease (ESRD). Hypertension is thought to be a significant modifying factor in the progression of renal failure in ADPKD. A number of genetic variations involved in renin-angiotensin-aldosterone system (RAAS) pathway genes have clinical or physiological impacts on pathogenesis of hypertension-induced ESRD in ADPKD. Information on RAAS pathway gene polymorphisms and their association with ESRD and ADPKD, published till March 2013, was collected using MEDLINE search. The present review deals with RAAS gene polymorphisms focused on hypertension-induced ESRD in ADPKD in different populations. The results were inconclusive and limited by heterogeneity in the study designs and the population stratification. In lieu of applying next generation sequencing technologies to study complex diseases, it is also possible to apply the same to unravel the complexity of ESRD in ADPKD. PMID:25001132
Ramanathan, Gnanasambandan; Elumalai, Ramprasad; Periyasamy, Soundararajan; Lakkakula, Bhaskar
Novel p.M96T variant of NRL and shRNA-based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa.
Mutations in the gene encoding the transcription factor neural retina leucine zipper (NRL) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone-rod homeobox (CRX), to transactivate a human rhodopsin (RHO) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family. The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL-linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time. PMID:21981118
Hernan, I; Gamundi, M J; Borrŕs, E; Maseras, M; García-Sandoval, B; Blanco-Kelly, F; Ayuso, C; Carballo, M
A case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) coexisting with pervasive developmental disorder harboring SCN1A mutation in addition to CHRNB2 mutation.
We report a case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with several characteristics distinct from previously reported cases, in which genetic studies identified mutations in two different genes. This case differed from typical ADNFLE with respect to the following: (1) slightly younger onset and refractory to antiepileptic drugs and (2) borderline intellectual functioning and coexistence of pervasive developmental disorder from infancy. Genetic testing revealed a novel mutation and a silent substitution in SCN1A (c.4285G>T, A1429S and c.4371G>C, silent) in addition to a known mutation in CHRNB2 (c.1200C>G, I312M). SCN1A is a gene that codes for the voltage-dependent sodium channel ?1 subunit and has been implicated in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy in infancy. However, the relation between SCN1A and ADNFLE is unknown. We report the clinical course and symptomatic characteristics of this case although the relationship between ADNFLE mutation and SCN1A mutation remains to be elucidated. PMID:23032131
Sone, Daichi; Sugawara, Takayuki; Sakakibara, Eisuke; Tomioka, Yu; Taniguchi, Go; Murata, Yoshiko; Watanabe, Masako; Kaneko, Sunao
Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B-lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with ?3?1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD.
Qin, Shan; Taglienti, Mary; Nauli, Surya M.; Contrino, Leah; Takakura, Ayumi; Zhou, Jing; Kreidberg, Jordan A.
Autosomal Dominant Polycystic Kidney Disease
... known, NIH-supported researchers have studied how these genes are involved in basic biological processes within kidney cells, and are exploring new avenues of investigation to understand how mutations might cause kidney cysts. The NIH funded two large clinical studies of ...
Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa
Purpose The purpose of this project was to determine the spectrum and frequency of mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) that cause autosomal dominant retinitis pigmentosa (adRP). Methods A well-characterized adRP cohort of 251 families was tested for mutations in the exons and intron/exon junctions of SNRNP200 using fluorescent dideoxy sequencing. An additional 21 adRP families from the eyeGENE® Network were tested for possible mutations. Bioinformatic and segregation analysis was performed on novel variants. Results SNRNP200 mutations were identified in seven of the families tested. Two previously reported mutations, p.Arg681Cys and p.Ser1087Leu, were found in two families each. One family had the previously reported p.Arg681His mutation. Two novel SNRNP200 variants, p.Pro682Ser and p.Ala542Val, were also identified in one family each. Bioinformatic and segregation analyses suggested that these novel variants are likely to be pathogenic. Clinical examination of patients with SNRNP200 mutations showed a wide range of clinical symptoms and severity, including one instance of non-penetrance. Conclusions Mutations in SNRNP200 caused 1.6% of disease in our adRP cohort. Pathogenic mutations were found primarily in exons 16 and 25, but the novel p.Ala542Val mutation in exon 13 suggests that variation in other genetic regions is also responsible for causing dominant disease. SNRNP200 mutations were associated with a wide range of clinical symptoms similar to those of individuals with other splice-factor gene mutations.
Sullivan, Lori S.; Avery, Cheryl E.; Sasser, Elizabeth M.; Roorda, Austin; Duncan, Jacque L.; Wheaton, Dianna H.; Birch, David G.; Branham, Kari E.; Heckenlively, John R.; Sieving, Paul A.; Daiger, Stephen P.
Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.
Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. PMID:21538838
Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda; Johansen, Ida R; Pandya, Arti; Welch, Katherine O; Norris, Virginia W; Arnos, Kathleen S; Bitner-Glindzicz, Maria; Emery, Sarah B; Mets, Marilyn B; Fagerheim, Toril; Eriksson, Kristina; Hansen, Lars; Bruhn, Helene; Möller, Claes; Lindholm, Sture; Ensgaard, Stefan; Lesperance, Marci M; Tranebjaerg, Lisbeth
A Truncated Form of Rod Photoreceptor PDE6 ?-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the ?-Subunit
Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin ?-subunit (GNAT1), and cGMP phosphodiesterase type 6 ?-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6?1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6?1-313. We found that PDE6?1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory ?-subunit (P?), and interferes with the inhibition of normal PDE6?? catalytic subunits by P?. Moreover, both truncated forms of the PDE6? protein, PDE6?1-313 and PDE6?1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results i