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B. Wissinger, M. Papke, S. Tippmann, S. Kohl, BCM Clinical Study Group; Genotypes in Blue Cone Monochromacy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4609.
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© ARVO (1962-2015); The Authors (2016-present)
To study the molecular basis and prevalence of different mutations in the red/green opsin gene cluster in a large series of patients with blue cone monochromacy (BCM).
The structure of the red/green opsin gene cluster was analyzed in 40 independent BCM patients by means of PCR amplification, PCR/RFLP, DNA sequencing and Southern Blot hybridizations. X chromosome inactivation assays were done for the methylation sensitive markers ARC and DXS6673E using DNA isolated from venous blood samples.
In 12 patients we found deletions of various sizes that encompass either the locus control region (LCR) or the LCR and parts of the opsin genes itself. Single red or red/green hybrid opsin genes that carry the known Cys203Arg mutations were present in 18 patients. However we observed considerable opsin gene sequence variability in this group which excludes a common founder mutation event. In addition we identified the Cys203Arg in 9 subjects with multiple opsin genes where all copies harbour this mutation. Finally we identified one patient with a single red opsin gene that carries a new nonsense mutation (W90X). In 4 carrier females with reduced visual function we were able to show preferential inactivation of the non–mutant X chromosome.
The presence of the Cys203Arg mutation was the most prevalent cause of BCM that accounted for more than 2/3 of all cases in our sample. Yet there is considerable genetic heterogeneity in such cases with respect to opsin gene copy number and the identity of the mutated gene copy/copies. We therefore propose that unequal homologous recombination is the driving force for the multiple independent occurrence of this genotype. We also provide evidence that skewed X inactivation may result in reduced visual function in BCM carrier females.
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