PMC3501959_01
Liver biopsy findings in patients with COACH syndrome. (A) Ductal plate malformation, fetus with MKS: the portal triad with ductal plate malformation has a ring of irregularly shaped and dilated bile duct structures that parallel the limiting plate. Trichrome, 150x. (B) Normal liver, 4 years: the portal triad contains a bile duct (lower left lumen), hepatic artery (lower right lumen) and portal vein (upper lumen) within a minimal amount of supporting fibrocollagen. Trichrome, 300x. (C) UW65, 11 months: the portal triad is expanded by minimal fibrosis and too many duct profiles, located both at the limiting plate and within the connective tissue. Trichrome, 200x. (D) UW65, 9 years: the portal triad has moderate fibrosis and an excess of bile ducts and hepatic artery branches with only minimal inflammation. Trichrome, 200x. (E) UW49, 10 years: the explanted liver has dense portal fibrosis that extends between triads and focally forms nodules. Trichrome, 20x. (F) UW49, 10 years: a portal triad in the explant shows moderate fibrosis and several irregular bile duct profiles. Trichrome, 300x. (G) UW04-3, 5 years: the liver biopsy has intact lobular architecture with portal fibrosis and occasional septa bridging portal areas. Trichrome, 20x. (H) UW04-3, 5 years: a representative portal area shows several profiles of bile ducts and hepatic artery branches within dense fibrocollagen; central clear lumen is a normal portal vein branch. Trichrome, 300x.
nihms-267872-f0001.jpg
PMC3501959_03_nihms-267872-f0001.jpg
F1
The liver demonstrated mild to moderate portal fibrosis with focal portal-portal bridging without inflammation or cholestasis (figure 1G); many triads contained an excess number of ducts (figure 1H).
Facial features, brain imaging and mutations for UW65 and UW49. (A) UW65 at 11 months of age. (B and C) Sagittal T1 weighted and axial T2 weighted brain magnetic resonance images demonstrating the molar tooth sign. (D) UW65 at 9 years of age. (E) MKS3 sequence tracings for UW65. (F) UW49 at 20 years of age. Photographs printed with permission from the families.
nihms-267872-f0002.jpg
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F2
This 22.5-year-old female (UW49), briefly reported in Gorden et al (2008), has speech dyspraxia, reads at the 6th grade level, and uses a wheelchair for mobility (figure 2F).
PMC3501959_02
Liver biopsy findings in patients with COACH syndrome. (A) Ductal plate malformation, fetus with MKS: the portal triad with ductal plate malformation has a ring of irregularly shaped and dilated bile duct structures that parallel the limiting plate. Trichrome, 150x. (B) Normal liver, 4 years: the portal triad contains a bile duct (lower left lumen), hepatic artery (lower right lumen) and portal vein (upper lumen) within a minimal amount of supporting fibrocollagen. Trichrome, 300x. (C) UW65, 11 months: the portal triad is expanded by minimal fibrosis and too many duct profiles, located both at the limiting plate and within the connective tissue. Trichrome, 200x. (D) UW65, 9 years: the portal triad has moderate fibrosis and an excess of bile ducts and hepatic artery branches with only minimal inflammation. Trichrome, 200x. (E) UW49, 10 years: the explanted liver has dense portal fibrosis that extends between triads and focally forms nodules. Trichrome, 20x. (F) UW49, 10 years: a portal triad in the explant shows moderate fibrosis and several irregular bile duct profiles. Trichrome, 300x. (G) UW04-3, 5 years: the liver biopsy has intact lobular architecture with portal fibrosis and occasional septa bridging portal areas. Trichrome, 20x. (H) UW04-3, 5 years: a representative portal area shows several profiles of bile ducts and hepatic artery branches within dense fibrocollagen; central clear lumen is a normal portal vein branch. Trichrome, 300x.
nihms-267872-f0001.jpg
PMC3501959_03_nihms-267872-f0001.jpg
F1
The liver demonstrated mild to moderate portal fibrosis with focal portal-portal bridging without inflammation or cholestasis (figure 1G); many triads contained an excess number of ducts (figure 1H).
Facial features, brain imaging and mutations for UW65 and UW49. (A) UW65 at 11 months of age. (B and C) Sagittal T1 weighted and axial T2 weighted brain magnetic resonance images demonstrating the molar tooth sign. (D) UW65 at 9 years of age. (E) MKS3 sequence tracings for UW65. (F) UW49 at 20 years of age. Photographs printed with permission from the families.
nihms-267872-f0002.jpg
PMC3501959_02_nihms-267872-f0002.jpg
F2
This 22.5-year-old female (UW49), briefly reported in Gorden et al (2008), has speech dyspraxia, reads at the 6th grade level, and uses a wheelchair for mobility (figure 2F).
PMC3501959_03
Liver biopsy findings in patients with COACH syndrome. (A) Ductal plate malformation, fetus with MKS: the portal triad with ductal plate malformation has a ring of irregularly shaped and dilated bile duct structures that parallel the limiting plate. Trichrome, 150x. (B) Normal liver, 4 years: the portal triad contains a bile duct (lower left lumen), hepatic artery (lower right lumen) and portal vein (upper lumen) within a minimal amount of supporting fibrocollagen. Trichrome, 300x. (C) UW65, 11 months: the portal triad is expanded by minimal fibrosis and too many duct profiles, located both at the limiting plate and within the connective tissue. Trichrome, 200x. (D) UW65, 9 years: the portal triad has moderate fibrosis and an excess of bile ducts and hepatic artery branches with only minimal inflammation. Trichrome, 200x. (E) UW49, 10 years: the explanted liver has dense portal fibrosis that extends between triads and focally forms nodules. Trichrome, 20x. (F) UW49, 10 years: a portal triad in the explant shows moderate fibrosis and several irregular bile duct profiles. Trichrome, 300x. (G) UW04-3, 5 years: the liver biopsy has intact lobular architecture with portal fibrosis and occasional septa bridging portal areas. Trichrome, 20x. (H) UW04-3, 5 years: a representative portal area shows several profiles of bile ducts and hepatic artery branches within dense fibrocollagen; central clear lumen is a normal portal vein branch. Trichrome, 300x.
nihms-267872-f0001.jpg
PMC3501959_03_nihms-267872-f0001.jpg
F1
The liver demonstrated mild to moderate portal fibrosis with focal portal-portal bridging without inflammation or cholestasis (figure 1G); many triads contained an excess number of ducts (figure 1H).
MKS3 mutations in COACH and Meckel syndromes. MKS3 encodes a 995 amino acid predicted protein with a signal peptide (sig), cysteine rich region, three transmembrane (TM) domains and a coiled-coil (CC) domain. Mutations identified in JSRD/COACH patients are listed above the protein diagram while mutations found in MKS patients are listed below. Previously unreported mutations are indicated with an asterix (*) and mutations also observed by Brancati et al are indicated with a plus sign (+).
nihms-267872-f0003.jpg
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F3
MKS3 mutations were distributed throughout the protein (figure 3), with the majority of the missense mutations located in the N-terminal extracellular domain.