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

To describe the genetic basis of an autosomal dominant vitreoretinopathy in a large French-Canadian kindred.

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.

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.

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.