title: Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome.
abstract: OBJECTIVE
  To report a 3-generation white family clinically diagnosed variably with Wagner, Stickler, and Jansen syndromes and screened for sequence variants in the COL2A1 and CSPG2 genes. Wagner syndrome is an autosomal dominant vitreoretinopathy with a predisposition to retinal detachment and cataracts. It has significant phenotypic overlap with allelic Jansen syndrome and ocular Stickler syndrome type 1. Sticker syndrome type 1 maps to chromosome 12q13.11-q13.2, with associated COL2A1 gene mutations. Wagner syndrome maps to chromosome 5q13-q14 and is associated with mutations in CSPG2 encoding versican, a proteoglycan present in human vitreous.
  
  
  METHODS
  Genomic DNA samples derived from venous blood were collected from all family members. Complete sequencing of COL2A1 was performed on a proband. Primers for polymerase chain reaction and sequencing were designed to cover all exon and intron-exon boundaries. Direct sequencing of CSPG2 was performed on all family member samples.
  
  
  RESULTS
  No detectable COL2A1 mutations were noted, making the diagnosis of ocular Stickler syndrome highly unlikely for this family. A unique base pair substitution (c.9265 + 1G>T) in intron 8 of the CSPG2 gene cosegregating with disease status was identified. This mutation occurred in a highly conserved previously reported splice site with a similar base pair substitution (G>A). Direct sequencing of this splice site mutation in 107 unrelated external controls revealed no variants, supporting the rarity of this base pair change and its causation in Wagner syndrome. This novel base pair substitution is thought to cause the deletion of exon 8 and formation of a truncated protein product.
  
  
  CONCLUSIONS
  Mutation screening of CSPG2 in autosomal dominant vitreoretinopathy families is important for accurate diagnosis.
  
  
  CONCLUSIONS
  This study underscores the importance of obtaining extensive pedigree information and comparative ophthalmologic clinical information, as the phenotypic findings may vary greatly among independent family members. The study also affirms the paradigm shift from diagnosis assignment based on eponyms to that based on gene mutation type.
authors.affiliation: Duke University Eye Center, Durham, NC 27710, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ronan
authors.forename: Khanh-Nhat
authors.initials: KN
authors.lastname: Tran-Viet
authors.forename: Erica L
authors.initials: EL
authors.lastname: Burner
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Metlapally
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Toth
authors.forename: Terri L
authors.initials: TL
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D020029:Base Pairing / Q000235:genetics*; D002648:Child; D024043:Collagen Type II / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics*; D013577:Syndrome; D041623:Tomography, Optical Coherence; D053675:Versicans / Q000235:genetics*; D014822:Vitreous Body
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; C508322:VCAN protein, human; D053675:Versicans; D004247:DNA