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A. Gal, B. Fiebig, V. Szabo, S. Koinzer, J. Roider, B. H. F. Weber; Mutation of the Bestrophin Gene in the Classical Form of Autosomal Dominant Vitreoretinochoroidopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3281.
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© ARVO (1962-2015); The Authors (2016-present)
Autosomal dominant vitreoretinochoroidopathy (adVIRC) is a rare form of retinal dystrophy with less than a dozen families reported to date. Typical ophthalmological signs of the disease include circular peripheral pigmentary disturbances with discrete posterior border in the equatorial region, yellow-white preretinal dots, prominent vascular abnormalities, no significant nyctalopia, and normal electrooculogram and electroretinogram. Recently, five families have been described in which all affected members had the characteristic retinal findings and additionally had ocular developmental anomalies including nanophthalmos, congenital cataract, and angle closure glaucoma (adVIRC-plus). Three different missense mutations of the BEST1/VMD2 gene, mutated in Best macular dystrophy, have been suggested to cause this complex phenotype. The purpose of this study was to determine whether BEST1/VMD2 mutations are also causative for the classical adVIRC phenotype.
Linkage analysis and BEST1/VMD2 mutation screening was performed using 11 DNA samples of a German family with 5 affected members in 3 generations presenting with the classical adVIRC phenotype (family described by Roider et al, Retina, 17:294,1997).
Close linkage without recombination has been detected between the disease locus and two loci (D11S4191 and D11S987) mapped in the vicinity of BEST1/VMD2 as well as two BEST1/VMD2 intragenic SNPs. Subsequently we identified a c.704T>G mutation in exon 6 of the BEST1/VMD2 gene that co-segregated with the disease phenotype and should result in a Val-235-Gly change. At the same time, c.704T>G alters an exonic splicing regulatory element that leads to increased skipping of exon 6 (38% for the G allele vs 19% for the T allele) in an in vitro functional assay.
In adVIRC-plus, all three BEST1/VMD2 mutations identified also alter exonic splicing regulatory sequences and thereby interfere with correct splicing of the bestrophin mRNA. This was shown to result in exon skipping. We have now found a BEST1/VMD2 missense mutation in a family with classical adVIRC that also leads to exon skipping and thus suggests that this is a general molecular pathomechanism in adVIRC. Remarkably, two other missense mutations (c.703G>A/Val-235-Met and c.703G>C/Val-235-Leu) affecting the same BEST1/VMD2 codon as in the adVIRC family studied here underlie Best disease suggesting a highly specific genotype-phenotype correlation.
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