Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic

Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
Vision research (Impact Factor: 1.82). 09/2010; 50(19):1989-99. DOI: 10.1016/j.visres.2010.07.009
Source: PubMed


Blue cone monochromacy (BCM) is an X-linked condition in which long- (L) and middle- (M) wavelength-sensitive cone function is absent. Due to the X-linked nature of the condition, female carriers are spared from a full manifestation of the associated defects but can show visual symptoms, including abnormal cone electroretinograms. Here we imaged the cone mosaic in four females carrying an L/M array with deletion of the locus control region, resulting in an absence of L/M opsin gene expression (effectively acting as a cone opsin knockout). On average, they had cone mosaics with reduced density and disrupted organization compared to normal trichromats. This suggests that the absence of opsin in a subset of cones results in their early degeneration, with X-inactivation the likely mechanism underlying phenotypic variability in BCM carriers.

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    • "In subjects in whom no amplification of the LCR-core sequence was achieved, a possible LCR deletion was suspected. Three sequence tagged sites (STSs), located at intervals 7.5 kb, 8.4 kb, and 9.3 kb upstream of the L-gene transcription initiation site, were then amplified to determine the approximate upstream extent of the deletion, as described previously (Carroll et al., 2010). If no product was obtained for the STSs the first exons of the genes flanking the opsin array, MECP2 and TKTL, were amplified to evaluate the extent of the deletion (primer sequences available on request). "
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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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    • "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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    • "The normal foveal and parafoveal cone mosaic has been well described as being triangular (hexagonally packed) both in histological [47–49] and more recently, using in vivo imaging tools [25,43]. Given the normal variation in cone density, these metrics have also been employed to examine disruptions in mosaic regularity caused by retinal disease [21,23,51]. Shown in Fig. 5 "
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