A -2 → G transition at the 3′ acceptor splice site of IVS17 characterizes the COL2A1 gene mutation in the original stickler syndrome kindred

C. J. Williams, A. Ganguly, E. Considine, S. McCarron, D. J. Prockop, C. Walsh-Vockley, V. V. Michels

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57 Scopus citations

Abstract

Hereditary progressive arthro-ophthalmopathy, or "Stickler syndrome," is an autosomal dominant osteochondrodysplasia characterized by a variety of ocular and skeletal anomalies which frequently lead to retinal detachment and precocious osteoarthritis. A variety of mutations in the COL2A1 gene have been identified in "Stickler" families; in most cases studied thus far, the consequence of mutation is the premature generation of a stop codon. We report here the characterization of a COL2A1 gene mutation in the original kindred described by Stickler et al. [1965]. Conformational sensitive gel electrophoresis (CSGE) [Ganguly et al., [1993] was used to screen for mutations in the entire COL2A1 gene in an affected member from the kindred. A prominent heteroduplex species was noted in the polymerase chain reaction (PCR) product from a region of the gene including exons 17 to 20. Direct sequencing of PCR-amplified genomic DNA resulted in the identification of a base substitution at the A -2 position of the 3′ splice acceptor site of IVS17. Sequencing of DNA from affected and unaffected family members confirmed that the mutation segregated with the disease phenotype. Reverse transcriptase-PCR analysis of poly A+ RNA demonstrated that the mutant allele utilized a cryptic splice site in exon 18 of the gene, eliminating 16 bp at the start of exon 18. This frameshift eventually results in a premature termination codon. These findings are the first report of a splice site mutation in classical Stickler syndrome and they provide a satisfying historical context in which to view COL2A1 mutations in this dysplasia.

Original languageEnglish (US)
Pages (from-to)461-467
Number of pages7
JournalAmerican Journal of Medical Genetics - Seminars in Medical Genetics
Volume63
Issue number3
DOIs
StatePublished - 1996

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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