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B. Wissinger, S. Schaich, C. Wolf, H. Jägle, F. Cremers, H. Dollfus, B. Varsanyi, T. Rosenberg, E. Zrenner, S. Kohl; Large Deletions of the KCNV2 Gene in Patients With Cone Dystrophy and Supernormal Rod Response. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3743.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the molecular genetics and disease mechanism of Cone Dystrophy with Supernormal Rod Response (CDSRR) that is linked to the KCNV2 gene
The KCNV2 gene and flanking SNPs were analyzed by DNA sequencing. Gene dosage analyses were carried out by means of TaqMan probe based realtime PCR and Nimblegen CGH array technology. Deletion junction fragments were obtained from Long Distance (LD) PCR amplifications and breakpoints covered by DNA sequencing.
In a screen for KCNV2 mutations in patients with CDSRR and similar type of retinal disorders we found two unrelated subjects with a homozygous deletion covering ~ 9 kb of genomic DNA sequence including most parts of exon 1 and intron 1. Moreover we observed four independent patients with apparent homozygous point mutations that failed to segregate concordantly in the nuclear family. Using quantitative realtime PCR we could show a decrease in KCNV2 gene dosage in all of those patients. Applying loss of heterozygosity and segregation analysis of flanking SNP and microsatellite markers we were able to narrow the extent of the deletions in three subjects, that finally enabled amplification and sequencing of deletion junction fragments in two of the subjects. A further patient was investigated applying Nimblegen CGH arrays which allowed the identification of a ~ 70 kb whole gene deletion.
Based on our screening data we found larger deletions in 6 of 27 patients with KCNV2 mutations indicating that such genomic rearrangements have to be taken into consideration in the genetic diagnostics of CDSRR. Our data also demonstrate that a complete loss of KCNV2 is a common pathomechanism in CDSRR.
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