Characterization of a novel form of X-linked incomplete achromatopsia

Crognale, Michael A.; Fry, Michael; Highsmith, Jennifer; Hægerström-Portnoy, Gunilla; Neitz, Maureen; Neitz, Jay; Webster, Michael A.

doi:10.1017/s0952523804213384

Cited by 33 publications

(49 citation statements)

References 23 publications

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“…Consistent with the classical point of view has been the lack of detectable L-/M-cone function in three patients: one with a deletion genotype, and two patients with C203R missense mutations (Stockman et al, 1999). On the other hand, residual L-or M-cone function was found in a 23-year-old patient with the LIAVA type of mutation (Crognale et al, 2004), which is thought to cause abnormal splicing of exon 3 of the cone opsin gene (Ueyama et al, 2012), and in several young affected males in a family with a deletion genotype (Mizrahi-Meissonnier et al, 2010) very similar to the genotype of our Family 1. In patient P15, central vision was mediated by rods and S cones under darkadapted or standard ambient light conditions.…”

Section: Consequences Of Congenital Cone Opsin Deficiency On Conessupporting

confidence: 59%

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

et al. 2013

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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. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. 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 the 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.

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Section: Consequences Of Congenital Cone Opsin Deficiency On Conessupporting

confidence: 59%

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

et al. 2013

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“…We had previously reported a similar reduction in cone density in a dichromat whose condition was caused by the presence of an unusual combination of polymorphisms encoded by exon 3 of the M-pigment gene (''LIAVA'') (24). The same unusual sequence was associated with blue-cone monochromacy (25) and was also associated with a case of X-linked incomplete achromatopsia (26). In contrast to the C203R retina, the LIAVA retina had normal ONL thickness and reduced regularity of the remaining visible cones.…”

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confidence: 89%

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin

Carroll

Baraas

Wagner-Schuman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.color vision ͉ cone mosaic ͉ photopigment ͉ retinal imaging ͉ rhodopsin N ormal human color vision is trichromatic and derives from the presence of three spectrally distinct cone types: long-, middle-, and short-wavelength-sensitive (L, M, and S). Redgreen color vision defects are characterized by the absence of either L or M cone function and they affect about one in 12 Caucasian males. Inherited red-green defects can be linked to disruptions at the X-chromosome opsin gene locus, where the Land M-cone opsin genes reside in a head-to-tail array (1). Most of these disruptions involve gross gene rearrangements (2-6). However, it is becoming appreciated that missense mutations underlie a significant proportion of red-green defects (5-8). This raises the question of what impact these missense mutations have on the viability of the cones.Some insight comes from rhodopsin. There are Ͼ130 distinct rhodopsin mutations, involving at least 89 sites within the molecule (data compiled from refs. 9-17.) With rare exception (e.g., refs. 9 and 18), each of these mutations has been associated with either retinitis pigmentosa (RP) or congenital stationary night blindness. Rhodopsin and the cone opsins have structural similarities and similar functional demands. Thus, it is reasonable to hypothesize that mutations in the cone opsins homologous to those in rhodopsin that cause retinitis pigmentosa would affect the viability of the cones.The most common missense mutation in the cone opsins is a substitution of cytosine for thymine at nucleotide position 1101, which corresponds to a substitution of arginine for cysteine at amino acid position 203 (C203R) (Fig. S1). The corresponding mutation in rhodopsin (C187Y) disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentos...

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“…This same haplotype was subsequently associated with XLCD and BCM in several studies. [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.…”

Section: Genetic Mechanisms Of X-linked Opsin Disordersmentioning

confidence: 99%

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

2016

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My interest in inherited eye disease was initiated at the genetic outreach clinics conducted by the University of Cape Town (UCT) Department of Human Genetics at schools for visually and hearing-impaired children in the Western Cape. As a clinical registrar from 1992 to 1998, I accom panied Prof. Peter Beighton on numerous clinics, where I developed a fascination for understanding the genetic mechanisms underlying the sensory deficits affecting many of the children and their families. This led to a research initiative into the molecular genetics of profound childhood deafness in South Africa BackgroundMutations in the human long wavelength-and middle wavelengthsensitive cone opsin genes cause several X-linked cone vision defects including red-green colour blindness (MIM 303800, MIM 303900), X-linked cone dysfunction (MIM 300843), blue cone monochromacy (BCM; MIM 303700) and X-linked cone dystrophy (COD5; MIM 303700). [1][2][3][4][5] These allelic X-linked cone opsin disorders display wide inter-and intrafamilial variability. However, in the majority the visual defect is non-progressive. A few, conversely, show signs of deterioration with increasing visual impairment, macular atrophy, retinal pigmentation and electroretinographic (ERG) dysfunction of S cones and rods. [4][5][6][7][8][9] In these it appears that the presence of dysfunctional opsin results in degeneration of the photoreceptor. 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. X-linked cone photoreceptor disordersThe photoreceptor layer of the retina is composed of a mosaic of L (red), M (green) and S (blue) cones, interspersed by rods. Cones are most abundant in the central retina and are responsible for colour vision, daylight vision and high visual acuity, while rods are responsible for peripheral and low-light vision. Normal human trichromatic colour vision requires three functioning classes of cone, each characterised by a constituent photopigment with a specific range of light sensitivity. Photopigments are comprised of an opsin protein linked to a light-sensitive chromophore and the spectral sensitivity of the pigment is determined by the amino acid sequence of the opsin.[1] Stimulation of the photopigment generates an electrical signal that is processed with signals from all three cone types before the combination is interpreted as trichromatic colour perception in humans. Loss of one cone type results in the dichromatic colour vision disorders protanopia (loss of functional L cones) and deuteranopia (loss of functional M cones).Both the L and M cone opsin genes (OPN1LW and OPN1MW) are located in a head-to-tail arrangement on chromosome Xq28, and loss of both L and M cone types causes X-linked BCM, alternatively known as incomplete achromatopsia. [1,4] Affected individuals have severe loss of colou...

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Characterization of a novel form of X-linked incomplete achromatopsia

Cited by 33 publications

References 23 publications

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin

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

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