X-Linked Cone Dystrophy Caused by Mutation of the Red and Green Cone Opsins

Jessica C Gardner,Tom R Webb,Naheed Kanuga,Anthony G Robson,Graham E Holder,Andrew Stockman,Caterina Ripamonti,Neil D Ebenezer,Olufunmilola Ogun,Sophie Devery,Genevieve A Wright,Eamonn R Maher,Michael E Cheetham,Anthony T Moore,Michel Michaelides,Alison J Hardcastle

doi:10.1016/j.ajhg.2010.05.019

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).

Highlights

Subjects and MethodsX-linked cone dystrophy (XLCOD) and X-linked cone-rod dystrophy (XLCORD) are a heterogeneous group of disorders in which there is dysfunction and degeneration of cone photoreceptors, often followed by later rod dysfunction.[1]
Mutations in the RPGR gene (MIM 312610) on Xp21 are the most common known cause of XLCOD/XLCORD (MIM 304020; COD1/ CORDX1), and all of the reported mutations are found in exon ORF15.2–5 XLCORD (COD3/ COD4/CORDX3 [MIM 300476]) has been described in one family from Finland with a mutation in the CACNA1F gene (MIM 300110) on Xp11.23, and an additional locus has been reported to map within the interval bounded by markers DXS292 and DXS1113 on Xq27 (MIM 300085; COD2/CORDX2).[6,7]
The proximal part of this disease region overlaps the distal part of the XLCOD2 region on Xq27; in the XLCOD2 family, recombination excluded the opsin array on Xq28.7 The locus for XLCOD described here caused by mutations in the cone opsin genes has been assigned XLCOD5

Summary

Introduction

Subjects and MethodsX-linked cone dystrophy (XLCOD) and X-linked cone-rod dystrophy (XLCORD) are a heterogeneous group of disorders in which there is dysfunction and degeneration of cone photoreceptors, often followed by later rod dysfunction.[1].

Results

Conclusion