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Alexander M Dizhoor, Elena V Olshevskaya, Igor V Peshenko; Mutation in human retinal membrane guanylyl cyclase 1 (RetGC1, GUCY2D) associated with CORD6 deregulates cGMP synthesis in photoreceptors and causes progressive blindness in transgenic mouse model.. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in human GUCY2D gene coding for the retinal membrane guanylyl cyclase 1 (RetGC1) can cause dominant cone-rod degeneration (CORD6) in humans. Such mutations alter calcium sensitivity of the recombinant cyclase in vitro, by affecting RetGC1 interaction with the activator versus inhibitor forms of GCAPs. The purpose of this study was to create a transgenic mouse model for the GUCY2D-CORD6 retinal degeneration and to test the physiological predictions from the biochemical studies.
The RetGC1 cDNA coding for the CORD6-linked R838S mutation in the cyclase dimerization domain  was transgenically expressed in mouse rods under control of 4.2-kb opsin promoter. Dark-adapted mouse retinas aged 3-3.5 weeks were assayed for the expression of the transgene and calcium-sensitivity of cGMP synthesis. ERG recordings were performed on transgenic and non-transgenic siblings at various ages and the eyes were then subjected to morphological analyses.
Calcium sensitivity of RetGC regulation by GCAPs in the R838S mouse retinas was markedly shifted, so that RetGC remained active at higher free calcium concentrations than in wild type littermates. The right-shift in calcium sensitivity closely resembled that in a mouse model expressing Y99C GCAP1 mutant [2, 3]. The R838S mice displayed a progressive decrease in ERG responses between 1 and 6 months of age, accompanying degeneration of rods.
Consistent with the predictions based on the in vitro studies, in a mouse model expressing CORD6 form of a human RetGC1, the guanylyl cyclase remains activated by GCAPs at higher than normal free Ca2+ concentrations - the same physiological change that triggers, by elevating both cGMP and free Ca2+, photoreceptor degeneration in Y99C GCAP1 mouse model. The R838S RetGC1 mice can now be utilized as a model for addressing the mechanisms of degeneration caused by GUCY2D-CORD6 and potential gene therapy applications.References:  Ramamurthy et al. (2001) J Biol Chem. 276, 26218-29;  Olshevskaya et al (2004) J. Neuroscience 24, 6078-85;  Woodruff et al. (2007) J. Neuroscience 27:8805-15.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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