title: Identification of the genetic defect in the original Wagner syndrome family.
abstract: OBJECTIVE
  The aim of the present study was to determine the genetic defect in Wagner syndrome, a rare disorder belonging to the group of hereditary vitreoretinal degenerations. This disease has been genetically mapped to chromosome 5q14.3.
  
  
  METHODS
  Molecular analysis was performed in the progeny of the original pedigree described by Wagner in 1938. We searched for pathogenic mutations and their effects in two candidate genes, CSPG2 and EDIL3, which locate to the critical chromosomal interval. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to investigate potential splice defects of CSPG2 transcripts.
  
  
  RESULTS
  While no alterations were detected in the exons of EDIL3, several changes were identified in the CSPG2 gene. Only one of the novel changes, a heterozygous G to A substitution of the first nucleotide in intron 8, cosegregates with the disease phenotype. This change disrupts the highly conserved splice donor sequence. In blood cells of an index patient, we found CSPG2 transcripts with normally spliced exon 8/9 junction but also two additional CSPG2 transcripts, which were not detected in the control. One lacks the entire exon 8, while the other is missing only the last 21 bp of exon 8.
  
  
  CONCLUSIONS
  CSPG2 encodes versican, a large proteoglycan, which is an extracellular matrix component of the human vitreous and participates in the formation of the vitreous gel. The splice site mutation described here may lead to a complete lack of exon 8 in CSPG2 transcripts, which shortens the predicted protein by 1754 amino acids and leads to severe reduction of glycosaminoglycan attachment sites.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, University of Zurich, Zurich, Switzerland. kloeckener@medgen.unizh.ch
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Abdou
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Zimmermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000225:Adenine; D016022:Case-Control Studies; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D020090:Chromosome Segregation; D004274:DNA, Recombinant; D005091:Exons; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006147:Guanine; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000097:blood; D012162:Retinal Degeneration / Q000235:genetics*; D013577:Syndrome; D053675:Versicans; D014822:Vitreous Body
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D004274:DNA, Recombinant; D037181:Lectins, C-Type; D012333:RNA, Messenger; C508322:VCAN protein, human; D053675:Versicans; D006147:Guanine; D000225:Adenine