Mutations in the Retinal Guanylate Cyclase (RETGC-1) Gene in Dominant Cone-Rod Dystrophy

Kelsell, Rosemary E.; Gregory-Evans, Kevin; Payne, Annette; Perrault, Isabelle; Kaplan, Josseline; Yang, Ruey‐Bing; Garbers, David L.; Bird, Alan C.; Moore, Anthony T.; Hunt, David M.

doi:10.1093/hmg/7.7.1179

Cited by 201 publications

(126 citation statements)

References 33 publications

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“…CORD6 is typically diagnosed as an early-onset blinding disorder, frequently by 7 years of age, first as impaired central and color vision (cone function), later involving rods, by progressing to the peripheral visual field with age (34,35). Among the genes linked to CORD6 in multiple genetic studies (34,45,51,52), GUCY2D coding for a human RetGC1 has been found most frequently affected by substitutions in codon 838 replacing , were shown to cause a prominent shift in Ca 2ϩ sensitivity of the cyclase regulation by GCAP1 when heterologously expressed in cultured HEK293 (44 -46).…”

Section: The Arg 838 Mutation In Retgc1 Alters Physiology Of Photorecmentioning

confidence: 99%

“…Among the genes linked to CORD6 in multiple genetic studies (34,45,51,52), GUCY2D coding for a human RetGC1 has been found most frequently affected by substitutions in codon 838 replacing , were shown to cause a prominent shift in Ca 2ϩ sensitivity of the cyclase regulation by GCAP1 when heterologously expressed in cultured HEK293 (44 -46). However, the physiological effects of the Arg 838 substitutions in RetGC1 have not been demonstrated in mammalian photoreceptors.…”

Section: The Arg 838 Mutation In Retgc1 Alters Physiology Of Photorecmentioning

confidence: 99%

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The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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Edited by Roger ColbranSubstitutions of Arg 838 in the dimerization domain of a human retinal membrane guanylyl cyclase 1 (RetGC1) linked to autosomal dominant cone-rod degeneration type 6 (CORD6) change RetGC1 regulation in vitro by Ca 2؉ . In addition, we find that R838S substitution makes RetGC1 less sensitive to inhibition by retinal degeneration-3 protein (RD3). We selectively expressed human R838S RetGC1 in mouse rods and documented the decline in rod vision and rod survival. To verify that changes in rods were specifically caused by the CORD6 mutation, we used for comparison cones, which in the same mice did not express R838S RetGC1 from the transgenic construct. The R838S RetGC1 expression in rod outer segments reduced inhibition of cGMP production in the transgenic mouse retinas at the free calcium concentrations typical for dark-adapted rods. The transgenic mice demonstrated early-onset and rapidly progressed with age decline in visual responses from the targeted rods, in contrast to the longer lasting preservation of function in the non-targeted cones. The decline in rod function in the retina resulted from a progressive degeneration of rods between 1 and 6 months of age, with the severity and pace of the degeneration consistent with the extent to which the Ca 2؉ sensitivity of the retinal cGMP production was affected. Our study presents a new experimental model for exploring cellular mechanisms of the CORD6-related photoreceptor death. This mouse model provides the first direct biochemical and physiological in vivo evidence for the Arg 838 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.Retinal membrane guanylyl cyclase (RetGC) 2 is one of the key enzymes in vertebrate visual signaling. Rods and cones respond to light by closing cGMP-gated plasma membrane channels in the outer segment as cGMP becomes hydrolyzed by phosphodiesterase PDE6 and then re-open the channels, after PDE6 activity becomes quenched and cGMP becomes re-synthesized by RetGC (1-5). Two RetGC isozymes expressed in photoreceptors, , bind calcium-sensor proteins, GCAPs (7-12), which decelerate the cyclase activity at high intracellular calcium concentrations in the dark and accelerate it in the light, when the influx of calcium through the cGMP-gated channels is shut off (13)(14)(15)(16)(17)(18)(19). RetGC also binds retinal degeneration 3 (RD3) protein (20 -21), which prevents cyclase activation by GCAPs (22-23) and promotes accumulation of RetGC1 in the outer segments (21,24,25). RetGC1 (human gene GUCY2D) accounts for most of the cGMP synthesis in mammalian photoreceptors (26,27), therefore mutations in RetGC1 that disable the cyclase activity (28 -33) cause recessive blindness at birth, Leber congenital amaurosis type 1 (LCA1) (33), mostly a non-degenerative or partially degenerative (31, 32) loss-of-function hereditary retinal disease. Different from the LCA1 type of severe congenital blindness linked to the RetGC1 gene, cone-rod dystrophy type 6 (CORD6), is a progressive ear...

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Section: The Arg 838 Mutation In Retgc1 Alters Physiology Of Photorecmentioning

confidence: 99%

Section: The Arg 838 Mutation In Retgc1 Alters Physiology Of Photorecmentioning

confidence: 99%

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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“…2,3 Sixty RP causative gene mutations were found. 4 EYS is an important and common cause of RP in the Japanese, Spanish, British, Chinese, Israelis, and Palestinians.…”

Section: Introductionmentioning

confidence: 99%

Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure

Miyata

Ogino

Gotoh

et al. 2016

Eye

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Purpose To evaluate whether the length of the inner segment ellipsoid (ISe) band can be used as a prognostic factor for disease course in retinitis pigmentosa (RP) patients with EYS mutations by observation over a period of 5 years. Methods Twelve RP patients with EYS mutations were studied. The horizontal and vertical ISe length of the right eye was manually measured at five time points annually, using spectral domain optical coherence tomography. A regression line through the five points from baseline to the final measurement was drawn and the ratio of the length (%) at each point to the baseline length was calculated; the slope was defined as the rate of ISe shortening (%/year). The correlation between the rate of ISe shortening and age, visual acuity, and mean deviation (MD) value were evaluated. The intraclass correlation coefficient (ICC) for the measurements was calculated. Results The mean rate of ISe shortening was − 4.65 ± 2.89% per year and the decline was statistically significant. The rate of shortening was significantly negatively correlated with the baseline length (P = 0.046, r = 0.58), but not with the baseline age, visual acuity, and MD value. The ICC (2, 1) was 0.999. Conclusions ISe of all RP patients with EYS mutations shortened during the 5 years of annual observation. The measurement of the length of ISe is a simple and convenient method with high repeatability, and the length is a sensitive prognostic factor for the rate of ISe shortening in RP patients with EYS mutations.

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“…A dominant form of cone-rod dystrophy (CORD6) is associated with GC-E mutations in humans [201], and a naturally occurring null mutation in the chick GC-E gene causes autosomal recessive retinal degeneration [202]. These findings are related to the phenotype of GC-E null mice [199].…”

Section: Gc-e Null Micementioning

confidence: 99%

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

2001

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Mutations in the Retinal Guanylate Cyclase (RETGC-1) Gene in Dominant Cone-Rod Dystrophy

Cited by 201 publications

References 33 publications

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

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