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(Investigative Ophthalmology and Visual Science. 2006;47:3565-3572.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0141
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Erosive Vitreoretinopathy and Wagner Disease Are Caused by Intronic Mutations in CSPG2/Versican That Result in an Imbalance of Splice Variants

Arijit Mukhopadhyay,1,2 Konstantinos Nikopoulos,1,2 Alessandra Maugeri,1,2 Arjan P. M. de Brouwer,1 C. Eric van Nouhuys,3 Camiel J. F. Boon,4 Rahat Perveen,5 Hester A. A. Zegers,4 Dienke Wittebol-Post,6 Pieter R. van den Biesen,6 Saskia D. van der Velde-Visser,1 Han G. Brunner,1 Graeme C. M. Black,5 Carel B. Hoyng,4 and Frans P. M. Cremers1,2

1From the Departments of Human Genetics and 4Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; the 2Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands; 3Canisius-Wilhelmina Ziekenhuis, Nijmegen, The Netherlands; the 5Department of Clinical Genetics, Central Manchester and Manchester Children’s University Hospitals NHS Trust, Manchester, United Kingdom; and the 6Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, The Netherlands.

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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