Dataset Information

X-linked cone dystrophy caused by mutation of the red and green cone opsins.

ABSTRACT: X-linked cone and cone-rod dystrophies (XLCOD and XLCORD) are a heterogeneous group of progressive disorders that solely or primarily affect cone photoreceptors. Mutations in exon ORF15 of the RPGR gene are the most common underlying cause. In a previous study, we excluded RPGR exon ORF15 in some families with XLCOD. Here, we report genetic mapping of XLCOD to Xq26.1-qter. A significant LOD score was detected with marker DXS8045 (Z(max) = 2.41 [theta = 0.0]). The disease locus encompasses the cone opsin gene array on Xq28. Analysis of the array revealed a missense mutation (c. 529T>C [p. W177R]) in exon 3 of both the long-wavelength-sensitive (LW, red) and medium-wavelength-sensitive (MW, green) cone opsin genes that segregated with disease. Both exon 3 sequences were identical and were derived from the MW gene as a result of gene conversion. The amino acid W177 is highly conserved in visual and nonvisual opsins across species. We show that W177R in MW opsin and the equivalent W161R mutation in rod opsin result in protein misfolding and retention in the endoplasmic reticulum. We also demonstrate that W177R misfolding, unlike the P23H mutation in rod opsin that causes retinitis pigmentosa, is not rescued by treatment with the pharmacological chaperone 9-cis-retinal. Mutations in the LW/MW cone opsin gene array can, therefore, lead to a spectrum of disease, ranging from color blindness to progressive cone dystrophy (XLCOD5).

SUBMITTER: Gardner JC

PROVIDER: S-EPMC2896775 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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X-linked cone dystrophy caused by mutation of the red and green cone opsins.

Gardner Jessica C JC Webb Tom R TR Kanuga Naheed N Robson Anthony G AG Holder Graham E GE Stockman Andrew A Ripamonti Caterina C Ebenezer Neil D ND Ogun Olufunmilola O Devery Sophie S Wright Genevieve A GA Maher Eamonn R ER Cheetham Michael E ME Moore Anthony T AT Michaelides Michel M Hardcastle Alison J AJ

American journal of human genetics 20100624 1

X-linked cone and cone-rod dystrophies (XLCOD and XLCORD) are a heterogeneous group of progressive disorders that solely or primarily affect cone photoreceptors. Mutations in exon ORF15 of the RPGR gene are the most common underlying cause. In a previous study, we excluded RPGR exon ORF15 in some families with XLCOD. Here, we report genetic mapping of XLCOD to Xq26.1-qter. A significant LOD score was detected with marker DXS8045 (Z(max) = 2.41 [theta = 0.0]). The disease locus encompasses the co ...[more]

PMID: 20579627

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Project description:To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

Dataset Information

X-linked cone dystrophy caused by mutation of the red and green cone opsins.

Publications

X-linked cone dystrophy caused by mutation of the red and green cone opsins.

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