A-2-->G transition at the 3' acceptor splice site of IVS17 characterizes the COL2A1 gene mutation in the original Stickler syndrome kindred

Am J Med Genet. 1996 Jun 14;63(3):461-7. doi: 10.1002/(SICI)1096-8628(19960614)63:3<461::AID-AJMG9>3.0.CO;2-U.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Aged
  • Base Sequence
  • Child, Preschool
  • Codon, Terminator
  • Collagen / genetics*
  • Electrophoresis, Polyacrylamide Gel / methods
  • Eye Diseases / genetics*
  • Female
  • Humans
  • Infant, Newborn
  • Joint Diseases / genetics*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Myopia / genetics
  • Pedigree
  • Polymerase Chain Reaction / methods
  • RNA Splicing*
  • RNA, Messenger / genetics
  • Retinal Detachment / genetics*
  • Syndrome


  • Codon, Terminator
  • RNA, Messenger
  • Collagen