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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
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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

Alexander M Dizhoor, Elena V Olshevskaya and Igor V Peshenko
The Journal of biological chemistry, v 291(47), pp 24504-24516
18 Nov 2016
DOI: https://doi.org/10.1074/jbc.M116.755553
PMID: 27703005
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5114404View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open
url
https://doi.org/10.1074/jbc.M116.755553View
Published, Version of Record (VoR) Open

Abstract

Amino Acid Substitution Animals Blindness - genetics Blindness - metabolism Blindness - pathology Calcium - metabolism Calcium Signaling Cyclic GMP - genetics Cyclic GMP - metabolism Disease Models, Animal Guanylate Cyclase - genetics Guanylate Cyclase - metabolism Humans Mice Mice, Transgenic Mutation, Missense Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Retinal Rod Photoreceptor Cells - metabolism Retinal Rod Photoreceptor Cells - pathology
Substitutions of Arg 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 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 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 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.

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26 citations in Web of Science
25 citations in Scopus

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Web of Science research areas
Biochemistry & Molecular Biology
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