Stickler Syndrome (hereditary artho-opthalmopathy) is estimated to be the most common autosomal dominant connective tissue disease in North America. It occurs in approximately 1 in 10,000 births. It is typified by unique facial features, retinal pathology, and hearing defects. Mutations in the procollagen genes Col2A1, Col11A1 and Col11A2 have been implicated in 50-70% of affected families. We have completed genetic studies on 48 probands with Stickler syndrome for mutations in Col2A1 and Col11A1 with Conformation Sensitive Gel Electrophoresis (CSGE) and direct sequencing of heteroduplex containing fragments. The patients were enrolled through IRB-approved project 2003-086. Twenty four mutations in Col2A1 and 4 mutations in Col11A1 were detected. The majority of the mutations involve a premature termination codon or an altered splice site suggesting that haploinsufficiency is the predominant mechanism of disease. Only one case involved substitution of a glycine in the collagen helix with a bulkier amino acid, which is frequently seen in type II collagenopathies that lead to dwarfism. There were two mutations each in the N and C propeptides, and the remaining mutations were in the helical domain. Detailed genotype/phenotype analysis of 28 probands with identified mutations revealed that facial characteristics such as malar hypoplasia, broad nasal bridge or flat facial profile were seen in all affected persons. The appearance of cleft palate showed that inter and intra-familial variability exists in Sticklers Syndrome. All patients have ocular manifestations, comprised of vitreous or retinal changes. Hearing loss, femoral head failure, skeletal manifestations and premature osteoarthritis were variable but common findings. New phenotypic findings identified included growth deficiency in three young children with COL11A1 mutations, and aortic root enlargement in two children- one with a mutation in COL2A1 and the other in COL11A1. Frontal bossing and basilar invagination of the odontoid into the brainstem was identified in patients with COL11A1 mutations. No causative mutation has been indentified to date in 21 probands. Analysis of a candidate gene (Versican) has been completed with no mutations found. Another candidate gene, KCNJ13, is being studied in Dr. Hejtmancik's laboratory. Large families without mutations in known genes will be studied by linkage analysis to discover novel causative genes. Recent data indicate that imprinting of COL2A1 may be responsible for intra-familial variability of the Stickler phenotype. Pedigree analysis and molecular level studies are under way to confirm this hypothesis.

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