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L. Mizrahi-Meissonnier, L. Bida, E. Banin, D. Sharon; Novel Cone Opsin Gene Cluster Mutations in Israeli Patients With X-Linked Cone Deficiencies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3097.
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Blue Cone Monochromacy (BCM), which is caused by mutations affecting both the red and green opsin genes, is not easily distinguished clinically from cone and cone-rod dystrophies, particularly in young patients. Most patients with X-linked cone-deficiency (XLCD) suffer from diminished visual acuity, color vision defects, and impaired cone electroretinography (ERG). Two X-linked loci, harboring the RPGR gene and the red and green opsin gene cluster, are known to cause XLCD. Two other loci are known. The aim of the current study was to perform genetic and clinical evaluations of Israeli families with XLCD and to evaulate the involvement of the cone opsin genes in these conditions.
Clinical evaluation included detailed family history, full ophthalmologic exam, color vision testing and full-field ERG. Linkage analysis of 28 microsatellite markers covering the entire X-chromosome was performed. Mutation detection was performed by direct sequencing of PCR products.
We recruited a large Moroccan Jewish family with 28 males affected with XLCD. Twelve affected males were clinically evaluated and had varying degrees of nystagmus, markedly impaired visual acuity, normal to subnormal rod ERG responses, and severely reduced or extinct full-field ERG cone responses. Linkage analysis excluded most of the X-chromosome showing linkage to Xq28 harboring the cone opsin gene cluster. We developed a PCR-sequencing protocol for efficient and fast mutation screening of this gene. A novel large genomic deletion (46,217bp) affecting both opsin genes was identified. Consequently, we screened a set of 14 families with definite, probable or possible X-linked CD and found cone opsin mutations in 4 families. We identified a similar deletion in patients from one of these families. In a second family, we found a partial deletion of the red opsin gene together with a known C203R mutation in the green opsin gene. In two other families we identified a deletion of the green opsin gene which in itself cannot explain the CD phenotype. A search for additional cone opsin mutation/s is in progress.
We present here novel deletions affecting the red-green opsin cluster in families with X-linked CD. Our results support previous reports in which patients with BCM were clinically diagnosed with cone or cone-rod dystrophy, and the diagnosis was revised following the identification of mutations in the cone opsin genes. We propose that patients clinically diagnosed with X-linked CD should be routinely analyzed for mutations in the red-green opsin genes.
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