Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

Abstract

PurposeMutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction.MethodsWe recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family.ResultsThere were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array.ConclusionsOur findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus.

Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X

“…Color vision defect observed in LVAVA patients was rather to be accounted for by the absence of either the L-or the M-opsin gene within the first two positions of the L/M-opsin gene array. 26,27,43 This observation explains the normal color vision in our young patients and also the nonsyndromatous high myopia associating to the LVAVA haplotype in two Chinese families. 33,34 The LVAVA haplotype differs from other interchange haplotypes in another aspect as well.…”

“…In contrast to that, SD-OCT and adaptive optics scanning light ophthalmoscopy analysis showed disruption of the cone photoreceptor mosaic and degenerative changes in the macula of patients with only LVAVA haplotype indicating a progressive macular degeneration. 27,43 In contrast to that, LVAVA haplotype associated to nonsyndromic high myopia in two Chinese families. 33,34 However, the oldest family member (75-years old) having only light perception visual acuity was excluded from further clinical investigations due to senile cataract making any ophthalmologic examinations impossible in the first family.…”

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations

“…For example, for the patients reported by Patterson et al, 18 the standard deviation (SD) for refractive error was more than 5 times higher (SD = 5.27 diopters) for patients with an LIAVA opsin gene variant than for patients with an LVAVA opsin gene variant (SD = 0.91 diopters).…”

Adaptive optics imaging of inherited retinal diseases

“…However, there is also high variability in the appearance of the cone mosaic within brothers who share the same genotype, likely owing to variations in L:M cone ratio. 59 60 Cone density has been found to correlate with both axial length and the degree of myopia 60 ; however, systematic analysis of the relationship between these factors and the specific underlying L/M opsin variant is lacking, due to small numbers of subjects within each genotype group to date. Additionally, previous investigations employing AOSLO imaging have been cross-sectional, so there is a need for longitudinal studies to track larger genetically confirmed cohorts, both for BED and BCM, to determine natural history and thereby better establish the potential for intervention.…”