A Frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration

PURPOSE: To describe the genetic basis of an autosomal dominant vitreoretinopathy in a large French-Canadian kindred. METHODS: A clinical cohort study followed by laboratory-based genetic and molecular analysis. Thirty-two affected and 22 unaffected members of the kindred were examined. Candidate genes/regions for Wagner's disease and Stickler syndrome were tested for genetic linkage. Mutation analysis was carried out with direct PCR-based sequencing. RESULTS: Funduscopic examinations of 32 affected patients revealed optically clear vitreous, vitreous veils, and radial perivascular pigmentation. Spondyloarthropathies or craniofacial abnormalities were notably absent. There was a 53% rate of retinal detachments that required surgical intervention. Genetic linkage was obtained to COL2A1, the candidate gene for Stickler's type I. A frame shift mutation in exon 2, leading to early truncation of the protein (Cys57Stop), was detected. CONCLUSIONS: Wagner's disease in this large kindred has had devastating visual consequences. In affected individuals, we found a novel COL2A1 frame shift mutation in exon 2. The mutation arises in an exon that is selectively present in vitreous collagen mRNAs, but absent in cartilage mRNAs through tissue-specific alternative splicing. Tissue-specific alternative splicing of COL2A1 mRNAs thus provides an elegant biochemical mechanism for a clinical phenotype of Wagner's disease in this kindred.