A Frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner’s vitreoretinal degeneration - 02/09/11
, Brian C Leonard, MD a, Karim F Damji, MD, FRCSC a, Dennis E Bulman, PhD aAbstract |
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.
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| ☆ | This work was supported by a grant from the E.A. Baker Foundation (S.K.G. and K.F.D.) and the Canadian Institute of Health Research (D.E.B.). |
Vol 133 - N° 2
P. 203-210 - février 2002 Retour au numéro
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