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).

Curing Color Blindness--Mice and Nonhuman Primates

“…One day, gene therapy methods may be sufficiently safe and practical that it will be possible to treat people for whom color blindness is a detriment to their quality of life. However, red-green color blindness can also be caused by point mutations in the cone opsin genes (Winderickx et al 1992;Neitz et al 2004;Carroll et al 2009Carroll et al , 2012Wagner-Schuman et al 2010), which in some cases are associated with cone dystrophy (Gardner et al 2010;McClements et al 2013), leading to debilitating vision loss in addition to color vision deficits. It remains to be seen whether the gene therapy approach used in squirrel monkeys could rescue cone dystrophy caused by mutations in cone photopigment genes.…”

Cone opsins, colour blindness and cone dystrophy: Genotype-phenotype correlations

“…[16] Similarly, the missense mutation p.Trp177Arg that causes XLCD, also misfolds and is retained in the endoplasmic reticulum. [5] Toxic aggregation of the misfolded mutant protein may be the cause of photoreceptor cell death and a degenerative phenotype.…”

“…Interestingly, the variant was found within a region of identical sequence in the two genes, indicating that it had been transferred from the M gene to the L gene by means of a partial gene conversion, a process whereby sequence is transferred from one gene to another without any change occurring in the donor sequence. [5] Molecular genetics of the cone opsin gene array OPN1LW and OPN1MW are duplicated genes that arose from a single opsin primate ancestor. The genes retain 98% sequence similarity and their close proximity and nose-to-tail genetic arrangement results in frequent meiotic mispairing and non-homologous recombination, and less commonly, in gene conversion events.…”

“…[1][2][3][4][5] These allelic X-linked cone opsin disorders display wide inter-and intrafamilial variability. However, in the majority the visual defect is non-progressive.…”

“…A few, conversely, show signs of deterioration with increasing visual impairment, macular atrophy, retinal pigmentation and electroretinographic (ERG) dysfunction of S cones and rods. [4][5][6][7][8][9] In these it appears that the presence of dysfunctional opsin results in degeneration of the photoreceptor. Recent studies have shown that cone opsin disorders, with specific visual and retinal phenotypes, are caused by several different genetic mechanisms.…”