title: Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants.
abstract: 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.Cys203Arg) 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.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg 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.532A>G SNP, common to all three disease-associated haplotypes, appears to be principally responsible for this mutational mechanism.
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Gardner
authors.forename: Gerald
authors.initials: G
authors.lastname: Liew
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Quan
authors.forename: Burcu
authors.initials: B
authors.lastname: Ermetal
authors.forename: Hisao
authors.initials: H
authors.lastname: Ueyama
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.forename: Nele
authors.initials: N
authors.lastname: Schwarz
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Ravinder
authors.initials: R
authors.lastname: Chana
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Jan
authors.initials: J
authors.lastname: Liebelt
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Ruddle
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; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D055358:Cone Opsins / Q000235:genetics*; D023061:Gene Order; D020868:Gene Silencing; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D057898:Hemizygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D019721:Ophthalmoscopes; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D055358:Cone Opsins
keywords: OPN1LW; OPN1MW; blue cone monochromacy; cone dystrophy; opsin; splicing