title: The influence of pre-mRNA splicing on phenotypic modification in Stickler's syndrome and other type II collagenopathies.
abstract: OBJECTIVE
  This paper will illustrate how variation in the processing of mutant pre-mRNA can affect the phenotypic outcome of inherited disorders of type II collagen.
  
  
  METHODS
  Type 1 Stickler's syndrome is one of the different phenotypes resulting from mutations in COL2A1 (the type II collagenopathies). It is also the commonest, but often goes undiagnosed due to the variability of phenotypic features, which in some cases may consist of only abnormal vitreous development. Most cases of type 1 Stickler's syndrome are due to premature termination codons in the mRNA, resulting in haploinsufficiency. This leaves a conundrum as to why the disease is so variable. Using RT-PCR of illegitimate transcript and also minigenes, we have investigated how certain mutations can variably affect mRNA processing.
  
  
  RESULTS
  Here, we demonstrate and discuss how apparently similar mutations can have a dramatically different effect on splicing of the pre-mRNA, switching transcripts from ones which would be degraded by nonsense-mediated decay into messages that will be translated into mutant proteins that can exert a dominant-negative effect and ultimately modify the resulting phenotype.
  
  
  CONCLUSIONS
  Variability of Stickler's syndrome can, in part, be due to the variable effect that mutations have on the processing of the COL2A1 transcript.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK. ar204@cam.ac.uk
authors.forename: A J
authors.initials: AJ
authors.lastname: Richards
authors.forename: M P
authors.initials: MP
authors.lastname: Snead
mesh_terms: D001483:Base Sequence / Q000235:genetics; D003095:Collagen Diseases / Q000235:genetics* / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D013577:Syndrome; D014822:Vitreous Body / Q000002:abnormalities
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; D012322:RNA Precursors