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

Am J Ophthalmol. 2002 Feb;133(2):203-10. doi: 10.1016/s0002-9394(01)01339-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alternative Splicing / genetics*
  • Cohort Studies
  • Collagen Type II / genetics*
  • DNA Mutational Analysis
  • Exons / genetics
  • Eye Diseases / genetics
  • Eye Diseases / pathology
  • Eye Diseases / surgery
  • Eye Diseases, Hereditary / genetics*
  • Eye Diseases, Hereditary / pathology
  • Eye Diseases, Hereditary / surgery
  • Female
  • Frameshift Mutation*
  • Genetic Linkage
  • Humans
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Pedigree
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / pathology
  • Retinal Degeneration / surgery
  • Syndrome
  • Vitreous Body / pathology*

Substances

  • Collagen Type II
  • RNA, Messenger

Associated data

  • OMIM/108300