Variable Retinal Phenotypes Caused by Mutations in the X-Linked Photopigment Gene Array

Mizrahi-Meissonnier, Liliana; Merin, Saul; Banin, Eyal; Sharon, Dror

doi:10.1167/iovs.09-4592

Cited by 42 publications

(59 citation statements)

References 30 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 Conesmentioning

confidence: 88%

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 Conesmentioning

confidence: 88%

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

et al. 2013

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“…16 The remaining four subjects (JC_0347, JC_0564, JC_0118, KS_0577) had OPN1LW and OPN1MW mutations that fell into the newly discovered category involving intermixing of ancestral genes to produce L/M interchange mutations with deleterious combinations of nucleotides at normal polymorphic positions in exon 3. 7,8,10,13,19,24 All four of these subjects had a late-onset, progressive phenotype that was in stark contrast to that of the subjects with a C203R mutation or the To investigate the reduction in retinal thickness in more detail, we examined the thickness of the inner retina and the ONLþHFL from high-resolution horizontal cross sections (Fig. 1), and compared it to previously reported normative data.…”

Section: Different Genotype Classes Associated With Distinct Clinicalmentioning

confidence: 99%

“…These mutations can be placed into one of three categories: (1) mutations that produced random nonhomologous missense substitutions at single amino acid positions 1,3,12,16 ; (2) partial or complete deletion of an exon 15,23 ; and (3) a recently identified category involving intermixing of ancestral OPN1LW and OPN1MW genes to produce ''L/M interchange'' mutations with deleterious combinations of nucleotides at normal polymorphic positions. 7,8,10,13 While at least one L/M interchange mutation has been shown to directly cause cone malfunction (Greenwald SH, et al IOVS 2012;53:ARVO E-Abstract 4643), it was recently shown that in addition to any functional changes in the photopigment caused by the mutations, many of the L/M interchange mutations also interfere with recognition of exon 3 by the splicing mechanism. 24 Some of the variants incompletely interfere with splicing, so full-length mRNA is produced as well as the inappropriately spliced transcript.…”

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confidence: 99%

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

Carroll

Dubra

Gardner³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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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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“…One deleterious variant has the amino acids leucine, isoleucine, alanine, valine, and alanine at amino acid positions 153, 171, 174, 178 and 180, respectively, and is abbreviated LIAVA. This variant has been associated with a color vision deficiency and blue cone monochromacy (Carroll et al , 2004; Crognale et al , 2004; Neitz et al , 2004; Mizrahi-Meissonnier et al , 2010). A second variant that differs from LIAVA only at position 171, where it has valine instead of isoleucine (LVAVA), has been associated with high myopia, cone dysfunction, and cone dystrophy (Carroll et al , 2012; McClements et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant

et al. 2013

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Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease. Knockout/knock-in mice promise to make it possible to study how these deleterious cone opsin variants affect the structure, function, and viability of the cone photoreceptors. Ideally, we would like to evaluate different variants that cause vision disorders in humans against a control pigment that is not associated with vision disorders, and each variant should be expressed as the sole photopigment in each mouse cone, as is the case in humans. To evaluate the feasibility of this approach, we created a line of mice to serve as the control in the analysis of disease causing mutations by replacing exon 2 through 6 of the mouse M opsin gene with the corresponding cDNA for a human L opsin variant that is associated with normal vision. Experiments reported here establish that the resulting pigment, which differs from the endogenous mouse M opsin at 35 amino acid positions, functions normally in mouse cones. This pigment was evaluated in mice with and without co-expression of the mouse short wavelength (S) opsin. Here, the creation and validation of two lines of genetically engineered mice that can be used to study disease-causing variants of human L/M-opsins, in vivo, are described.

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Variable Retinal Phenotypes Caused by Mutations in the X-Linked Photopigment Gene Array

Cited by 42 publications

References 30 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

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

S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant

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