title: The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice.
abstract: Substitutions of Arg838in 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 Ca2+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 Ca2+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 Arg838substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.
authors.affiliation: From the Department of Research, Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania 19027. Electronic address: adizhoor@salus.edu.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dizhoor
authors.affiliation: From the Department of Research, Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania 19027.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Olshevskaya
authors.affiliation: From the Department of Research, Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania 19027.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Peshenko
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001766:Blindness / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D011956:Receptors, Cell Surface; D006162:Guanylate Cyclase; C484774:Gucy2d protein, mouse; D006152:Cyclic GMP; D002118:Calcium
keywords: GCAP; calcium-binding proteins; cyclic GMP (cGMP); eye; guanylate cyclase (guanylyl cyclase); photoreceptor; phototransduction; retina; retinal degeneration; vision