Mutational Hot Spot Potential of a Novel Base Pair Mutation of the CSPG2 Gene in a Family With Wagner Syndrome

Ronan, Shawn M.

doi:10.1001/archophthalmol.2009.273

Cited by 28 publications

(16 citation statements)

References 12 publications

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“…5 To date, all WS patients, for whom mutations have been identified, have been heterozygous for single-nucleotide substitutions in either the conserved splice acceptor site of intron 7 or the splice donor site of intron 8. 3,[6][7][8][9][10] Although the exact molecular pathogenesis of WS is not fully understood, it is clear that splicing is involved. Mutations in the intron 7 splice acceptor site can activate a cryptic splice site 21 base pairs into exon 8 generating aberrant transcripts.…”

Section: Introductionmentioning

confidence: 99%

Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome

et al. 2012

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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 À1G4C and c.9265 þ 2T4A) 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 þ 1G4A 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.

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Section: Introductionmentioning

confidence: 99%

Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome

et al. 2012

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“…The disease‐causing molecular defect for Wagner disease has been identified in 2005 [Miyamoto et al., ], in a Japanese family with a nucleotide substitution at the splice acceptor site of intron 7 of the VCAN gene ( VCAN ; MIM# 118661) affecting exon 8 splicing. During the 10 years following this discovery, 14 unrelated kindred with Wagner disease (other references given at the end) or erosive vitreoretinopathy have been reported with seven new mutations that invariably target the splice donor or acceptor sites of VCAN exon 8 [Miyamoto et al., ; Kloeckener‐Gruissem et al., ; Mukhopadhyay et al., ; Ronan et al., ; Brézin et al., ; Kloeckener‐Gruissem et al., ; Rothschild et al., ]. VCAN is a 110‐kb large gene, consisting of 15 exons coding for a chondroitin sulfate proteoglycan, named versican.…”

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confidence: 99%

Deletions OverlappingVCANExon 8 Are New Molecular Defects for Wagner Disease

Rothschild

Layet²,

Chen

et al. 2016

Human Mutation

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Wagner disease is a rare nonsyndromic autosomal-dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease-associated splice mutations. Next-generation sequencing (NGS), quantitative real-time PCR, and long-range PCR identified two deletions (3.4 and 10.5 kb) removing at least one exon-intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms. We showed that the 10.5-kb deletion occurred de novo, causing somatic mosaicism in the proband's mother who had an unusually mild asymmetrical phenotype. Therefore, exon 8 deletions are novel VCAN genetic defects responsible for Wagner disease, and VCAN mosaic mutations may be involved in the pathogenesis of Wagner disease with attenuated phenotype. NGS is then an effective screening tool for genetic diagnosis of Wagner disease, improving the chance of identifying all disease-causative variants as well as mosaic mutations in VCAN.

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“…Note the evolving facial features of pronounced broad forehead, mild hypertelorism, downslanting palpebral fissures, positive angle kappa, and pointed chin with age. (b) Top: Facial picture of published individual with VCAN mutation (Brezin et al, ; Chen et al, ; Kloeckener‐Gruissem et al, ; Miyamoto et al, ; Mukhopadhyay et al, ; Ronan et al, ; Rothschild et al, ). The major features include pronounced broad forehead, hypertelorism, downslanting palpebral fissures, positive angle kappa, and pointed chin.…”

Section: Case Presentationmentioning

confidence: 99%

“…Since this initial report, all pathogenic variants reported in VCAN have been splice site variants (donor or acceptor site), shown or predicted to result in skipping or splicing out of exon 8 from the mature vcan transcripts (Brezin et al, ; Chen et al, ; Kloeckener‐Gruissem, Bartholdi, Abdou, Zimmermann, & Berger, ; Kloeckener‐Gruissem et al, ; Miyamoto et al, ; Mukhopadhyay et al, ; Ronan et al, ; Rothschild et al, ). Exon 8 is the largest exon of the VCAN gene and is an integral part of two of the four major transcripts or protein isoforms expressed from the gene.…”

Section: Introductionmentioning

confidence: 99%

Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome

Ankala

Jain

Hubbard

et al. 2018

American J of Med Genetics Pt A

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Wagner syndrome and erosive vitreoretinopathy together constitute the phenotypic continuum of an autosomal dominant vitreoretinopathy, with clinical findings typically isolated to the eye. The disease is caused by pathogenic variants in the VCAN gene and all such variants reported to date are those that plausibly result in haploinsufficiency of exon 8 containing vcan transcripts. Here, we report the molecular findings and long-term follow-up of a 16-year-old female with a history of retinal detachments and pigmentary retinal changes. Next-generation sequencing and microarray analysis of 141 genes established a diagnosis of Wagner syndrome in this individual, by detection of an 11.7 kilobase (kb) deletion encompassing exon 8 of VCAN. In light of the emerging functions and roles of versican protein in human disease, we discuss how variants within exon 8 of the VCAN gene can be compared to those in exon 2 of the COL2A1 gene that cause atypical Stickler syndrome and propose that variants in other regions of the gene can be expected to present with a more systemic disease. The distinctive facial features and atypical gastrointestinal symptoms observed in this long-term follow-up study support the possibility that individuals with VCAN-related vitreoretinopathy may have extra-ocular clinical features.

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Mutational Hot Spot Potential of a Novel Base Pair Mutation of the CSPG2 Gene in a Family With Wagner Syndrome

Cited by 28 publications

References 12 publications

Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome

Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome

Deletions OverlappingVCANExon 8 Are New Molecular Defects for Wagner Disease

Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome

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