PMC4485893_01
Pedigree of the affected family.. Circles represent females and squares represent males. The proband is indicated by an arrow. Solid symbols indicate homozygosity for E26RfsX68, while half solid symbols indicate heterozygosity and open symbols non-carriers. The question mark in I.1 and II.3 indicate that genotype is not known. BMI, body mass index, in kg/m2, and age are as of day of examination. T2DM, Type 2 diabetes mellitus.
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The proband examined in this study was a 20 year old morbidly obese, Sudanese female, with childhood-onset obesity (current body mass index (BMI) 51.5 kg/m2), intellectual disability, newly diagnosed T2DM and hypogonadotrophic hypogonadism (Fig 2 and individual II.6 in Fig 1). Other family members: the proband' s mother; two sisters and two brothers (Fig 1), all had a history of mild obesity, with one brother (II.4) who achieved normal weight through lifestyle changes. Another unaffected sister (II.1) did not carry the deletion (Fig 1).
Clinical features of proband with homozygous truncating CPE mutation.. Photograph of proband carrying a homozygous truncating deletion of CPE. Specific written consent for the photograph and case details was obtained from proband and mother. At the time of examination, the proband had a weight of 130.2 kg and height of 1.59 m with body mass index (BMI) 51.5 kg/m2. There was some intellectual disability, for example despite adequate schooling she was unable to read or write words. She had newly diagnosed type 2 diabetes mellitus with fasting glucose 383 mg/dL, 21.1 mmol/L; HbA1c 114 mmol/mol, 12.6%) and hypogonadotrophic hypogonadism with primary amenorrhea (serum oestradiol 78 pmol/L [post-menopausal range <100 pmol/L], 21.2 pg/mL; LH 2.7 IU/L, FSH 2.0 IU/L). Serum hormone analysis excluded other causes of amenorrhoea including polycystic ovary syndrome and hyperprolactinaemia (testosterone 1.2 nmol/L (normal <2.7), 0.35 ng/mL (normal <0.78); normal androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS), prolactin). There was no history of depression or anxiety.
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The proband examined in this study was a 20 year old morbidly obese, Sudanese female, with childhood-onset obesity (current body mass index (BMI) 51.5 kg/m2), intellectual disability, newly diagnosed T2DM and hypogonadotrophic hypogonadism (Fig 2 and individual II.6 in Fig 1).
Location of c.76_98del; p. E26RfsX68 CPE mutation.. A: Schematic overview of the exons of CPE (Refseq: NM_001873). Dark shaded areas are UTRs and light grey areas are coding regions. B: Human CPE protein (UniprotKB: P16870). Location of the E26RfsX68 mutation is shown by the red diagonally striped region. Arrow shows the location of Arg283Trp. SP, signalling peptide; PP, pro-peptide. C: Indicative chromatogram of the deletion in the proband and the normal wild-type sequence. The deletion is indicated in red. Amino acid changes caused by the frameshift are shown above the chromatogram.
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An exact 7 nucleotide repeat (GGGCGCC) at the breakpoints, might indicate a microhomology-mediated deletion mechanism (Fig 3).
CPE mRNA expression levels.. Real time PCR analysis of CPE mRNA expression in blood samples from the proband (II.6), heterozygous sibling (II.5) and six controls. For controls mean +- SEM (standard error of the mean) is depicted. All analyses were conducted in triplicate.
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The value for normalised CPE expression in the heterozygous sibling was at the lower end of the range seen in the controls (Fig 4).