[HTML][HTML] Erosive vitreoretinopathy and wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants
A Mukhopadhyay, K Nikopoulos… - … & visual science, 2006 - arvojournals.org
A Mukhopadhyay, K Nikopoulos, A Maugeri, APM De Brouwer, CE Van Nouhuys, CJF Boon…
Investigative ophthalmology & visual science, 2006•arvojournals.orgpurpose. 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 …
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 …
Abstract
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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