title: 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).
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Gardner
authors.forename: Tom R
authors.initials: TR
authors.lastname: Webb
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Andrew
authors.initials: A
authors.lastname: Stockman
authors.forename: Caterina
authors.initials: C
authors.lastname: Ripamonti
authors.forename: Neil D
authors.initials: ND
authors.lastname: Ebenezer
authors.forename: Olufunmilola
authors.initials: O
authors.lastname: Ogun
authors.forename: Sophie
authors.initials: S
authors.lastname: Devery
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Wright
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D041321:Chromosomes, Human, X / Q000235:genetics; D055358:Cone Opsins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D008040:Genetic Linkage; D056426:Genetic Loci; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017433:Protein Structure, Secondary; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: D055358:Cone Opsins