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Three Different Cone Opsin Gene Array Mutational Mechanisms with Genotype–Phenotype Correlation and Functional Investigation of Cone Opsin Variants
Author(s) -
Gardner Jessica C.,
Liew Gerald,
Quan YingHua,
Ermetal Burcu,
Ueyama Hisao,
Davidson Alice E.,
Schwarz Nele,
Kanuga Naheed,
Chana Ravinder,
Maher Eamonn R.,
Webster Andrew R.,
Holder Graham E.,
Robson Anthony G.,
Cheetham Michael E.,
Liebelt Jan,
Ruddle Jonathan B.,
Moore Anthony T.,
Michaelides Michel,
Hardcastle Alison J.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22679
Subject(s) - biology , haplotype , genetics , exon , missense mutation , single nucleotide polymorphism , opsin , retinitis pigmentosa , locus (genetics) , gene , mutation , genotype , retinal , rhodopsin , biochemistry
Mutations in the OPN1LW ( L ‐) and OPN1MW ( M ‐)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the locus control region ( LCR ); missense mutation (p. C ys203 A rg) in an L ‐/ M ‐hybrid gene; and exon 3 single‐nucleotide polymorphism ( SNP ) interchange haplotypes in an otherwise normal gene array. Moderate‐to‐high myopia was observed in all mutation categories. Individuals with LCR deletions or p. C ys203 A rg mutations were more likely to have nystagmus and poor vision, with disease progression in some p. C ys203 A rg patients. Three disease‐associated exon 3 SNP haplotypes encoding LIAVA , LVAVA , or MIAVA were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 years having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here, we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW / OPN1MW :c.532 A > G SNP , common to all three disease‐associated haplotypes, appears to be principally responsible for this mutational mechanism.