The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic

The Eye Institute, Medical College of Wisconsin, 925 N. 87th Street, Milwaukee, WI, 53226, United States.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 11/2012; 53(13). DOI: 10.1167/iovs.12-11087
Source: PubMed


To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations.

Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array.

While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with "L/M interchange" mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic.

The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy.

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Available from: Michel Michaelides, Feb 06, 2015
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    • "In our cohort, patients with exon 3 interchange haplotypes commonly had a progressively worsening phenotype, including visual acuity reduction, with onset of macular atrophy after the age of 40, and electrophysiological evidence of progressive loss of cone function with increasing rod involvement over time. These results are in keeping with other reports showing that some patients with exon 3 interchange haplotypes have more severe outer retinal atrophy than patients with p.Cys203Arg mutations, and that these patients also report a progressive loss of visual function (Carroll et al., 2012). The interchange haplotype patients in the cohort, except S26 (who harbours the LVAVA haplotype), all developed symptoms in their first decade. "
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    ABSTRACT: Mutations in the OPN1LW (L-) and OPN1MW (M-) cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of colour 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 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.This article is protected by copyright. All rights reserved
    Human Mutation 08/2014; 35(11). DOI:10.1002/humu.22679 · 5.14 Impact Factor
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    • "BCM patients showed a severely disrupted foveal mosaic, consisting of a ring of sparsely packed, highly reflective bright cones and a second population of weakly reflecting photoreceptors, which were present throughout the foveola (Fig. 5F). The bright cones presumably correspond to S cones, and the central region lacking bright cones defines the extent of the S-cone-free zone at the center of the foveola; this has been noted in other patients with BCM (Carroll et al., 2012). The weakly reflecting cells may comprise both remnant L/M cones and rods, though it was not possible to differentiate subtypes within this population. "
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    ABSTRACT: Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. We studied a cohort of 20 BCM patients (ages 5-58) with large deletions in the red/green opsin gene array using in vivo histology with high resolution retinal imaging. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.
    Human gene therapy 09/2013; 24(12). DOI:10.1089/hum.2013.153 · 3.76 Impact Factor
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    • "The other two (JC_0120 & JC_0121) had an L/M opsin gene array in which there was a single gene encoding a mutant opsin, shown previously to result in cone degeneration [29]. Despite these genetic differences, all six individuals are expected to have early degeneration of a subset of their L/M cones; previous imaging results with AO have shown similar cone mosaic disruptions in all BCM carriers [21], [30]. "
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    ABSTRACT: Carriers of blue cone monochromacy have fewer cone photoreceptors than normal. Here we examine how this disruption at the level of the retina affects visual function and cortical organization in these individuals. Visual resolution and contrast sensitivity was measured at the preferred retinal locus of fixation and visual resolution was tested at two eccentric locations (2.5° and 8°) with spectacle correction only. Adaptive optics corrected resolution acuity and cone spacing were simultaneously measured at several locations within the central fovea with adaptive optics scanning laser ophthalmoscopy (AOSLO). Fixation stability was assessed by extracting eye motion data from AOSLO videos. Retinotopic mapping using fMRI was carried out to estimate the area of early cortical regions, including that of the foveal confluence. Without adaptive optics correction, BCM carriers appeared to have normal visual function, with normal contrast sensitivity and visual resolution, but with AO-correction, visual resolution was significantly worse than normal. This resolution deficit is not explained by cone loss alone and is suggestive of an associated loss of retinal ganglion cells. However, despite evidence suggesting a reduction in the number of retinal ganglion cells, retinotopic mapping showed no reduction in the cortical area of the foveal confluence. These results suggest that ganglion cell density may not govern the foveal overrepresentation in the cortex. We propose that it is not the number of afferents, but rather the content of the information relayed to the cortex from the retina across the visual field that governs cortical magnification, as under normal viewing conditions this information is similar in both BCM carriers and normal controls.
    PLoS ONE 02/2013; 8(2):e57956. DOI:10.1371/journal.pone.0057956 · 3.23 Impact Factor
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