Three Different Cone Opsin Gene Array Mutational Mechanisms; Genotype-Phenotype Correlation and Functional Investigation of Cone Opsin Variants

Abstract

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-/Mhybrid 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.

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

“…[21] The pathogenicity of exon 3 haplotypes was further established in a detailed study of BCM and XLCD phenotypes and genotypes in a British cohort of patients. [12] In this study, 41% of the affected males were found to have an unusual exon 3 haplotype, indicating that as a group, these haplotypes are a relatively common cause of opsin disorders and more frequent than either missense mutations or LCR deletions. LIAVA and LVAVA haplotypes were both found in the cohort in addition to a novel haplotype, MIAVA.…”

“…The IC haplotypes illustrate an unexpected genetic mechanism that appears to be a frequent cause of severe cone dysfunction in both monochromatic (BCM) and dichromatic (BED) colour vision disorders. [12,14] The effects of these haplotypes on splicing depends on the combination of variants, so some may be degenerative while others are not. LVAVA has a progressive visual phenotype that is reflected in additional damage to the S cones and rods neighbouring mutant L/M cones.…”

“…[17][18][19] A second rare haplotype of nucleotide variants (Table 1) translating to p.[153Leu; 171Val; 174Ala; 178Val; 180Ala] or LVAVA, has also been associated with XL cone dysfunction, [20] BCM and with cone dystrophy. [10,12,14] However, we now know that it is not the amino acid changes that are causing disease but the combinations of nucleotides. The single nucleotide variants comprising the LIAVA and LVAVA haplotypes are common (MAF >0.05 among OPN1LW OPN1MW chrXq28 n…”

“…[10,12] Subjects with p.Cys203Arg also display congenital loss of colour vision and most are stable, but some older individuals show evidence of macular changes. Subjects with p.Trp177Arg had a more gradual onset of visual disturbance but developed extensive macular dystrophy and cone photoreceptor loss.…”

“…Recent studies have shown that cone opsin disorders, with specific visual and retinal phenotypes, are caused by several different genetic mechanisms. [10][11][12] As a result, genotype-phenotype correlations are beginning to emerge that influence predictions of the course and severity of disease. …”