title: Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome.
abstract: Wagner syndrome (WS) is an autosomal dominant vitreoretinopathy affecting various ocular features and is caused by mutations in the canonical splice sites of the VCAN gene, which encodes the large chondroitin sulfate proteoglycan, versican. We report the identification of novel splice acceptor and donor-site mutations (c.4004-1G>C and c.9265+2T>A) in two large WS families from France and the United Kingdom. To characterize their pathogenic mechanisms we performed qRT-PCR experiments on RNA from patient-derived tissues (venous blood and skin fibroblasts). We also analyzed RNA from the original Swiss family reported by Wagner (who has the previously reported c.9265+1G>A mutation). All three mutations resulted in a quantitative increase of transcript variants lacking exons 7 and/or 8. However, the magnitude of the increase varied between tissues and mutations. We discuss altered balance of VCAN splice variants in combination with reduction in glycosaminoglycan protein modifications as possible pathogenic mechanisms.
authors: Institute of Medical Molecular Genetics, University of Zurich, Schwerzenbach, Switzerland. kloeckener@medgen.uzh.ch
authors: Barbara
authors: B
authors: Kloeckener-Gruissem
authors: John
authors: J
authors: Neidhardt
authors: István
authors: I
authors: Magyar
authors: Henri
authors: H
authors: Plauchu
authors: Jean-Christophe
authors: JC
authors: Zech
authors: Laurette
authors: L
authors: Morlé
authors: Sheila M
authors: SM
authors: Palmer-Smith
authors: Moira J
authors: MJ
authors: Macdonald
authors: Véronique
authors: V
authors: Nas
authors: Andrew E
authors: AE
authors: Fry
authors: Wolfgang
authors: W
authors: Berger
mesh_terms: D017398:Alternative Splicing; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D053675:Versicans / Q000235:genetics*
chemical_list: C508322:VCAN protein, human; D053675:Versicans