4.6 Article

Erosive vitreoretinopathy and Wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants

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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 47, 期 8, 页码 3565-3572

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ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.06-0141

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PURPOSE. Linkage intervals for erosive vitreoretinopathy (ERVR) and Wagner disease previously were found to overlap at 5q14.3. In a Japanese family with Wagner disease, a CSPG2/Versican splice site mutation (c. 4004-2A -> G) was recently reported that resulted in a 39-nucleotide exon 8 in-frame deletion. We investigated whether CSPG2/Versican was mutated in six Dutch families and one Chinese family with Wagner disease and in a family with ERVR. METHODS. In all families, extensive ophthalmic examinations, haplotype analysis of the 5q14.3 region, and sequence analysis of CSPG2/Versican were performed. The effects of splice site mutations were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR (QPCR). RESULTS. Three novel intron 7 sequence variants (c. 4004-5T -> C, c. 4004-5T -> A, c. 4004-1G -> A) were identified in seven families. The c. 4004-5T -> C variant was identified in four families with Wagner disease and a family with ERVR. The families were shown to carry the same 5q14.3 haplotype, strongly suggesting that this is a common Dutch founder variant. All three changes segregated with the disease in the respective families and were absent in 250 healthy individuals. In patients with the c. 4004-5T -> A and c. 4004-1G -> A variants, RT-PCR analysis of CSPG2/Versican showed activation of a cryptic splice site resulting in a 39-nt exon 8 in-frame deletion in splice variant V0. QPCR revealed a highly significant (P < 0.0001) and consistent increase of the V2 (> 38-fold) and V3 ( > 12-fold) splice variants in all patients with intron 7 nucleotide changes and in a Chinese Wagner disease family, in which the genetic defect remains to be found. CONCLUSIONS. Wagner disease and ERVR are allelic disorders. Seven of the eight families exhibit a variant in intron 7 of CSPG2/Versican. The conspicuous clustering of sequence variants in the splice acceptor site of intron 7 and the consistent upregulation of the V2 and V3 isoforms strongly suggest that Wagner disease and ERVR may belong to a largely overlooked group of diseases that are caused by mRNA isoform balance shifts, representing a novel disease mechanism.

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