GPR179 Is Required for Depolarizing Bipolar Cell Function and Is Mutated in Autosomal-Recessive Complete Congenital Stationary Night Blindness

NS Peachey, TA Ray, R Florijn, LB Rowe, T Sjoerdsma, S Contreras-Alcantara, K Baba, G Tosini, N Pozdeyev, PM Iuvone, P Bojang, JN Pearring, Huib Simonsz, M van Genderen, DG Birch, EI Traboulsi, A Dorfman, I Lopez, HN Ren, AFX GoldbergPM Nishina, P Lachapelle, MA McCall, RK Koenekoop, Arthur Bergen, M Kamermans, RG Gregg

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Abstract

Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG h-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.
Original languageUndefined/Unknown
Pages (from-to)331-339
Number of pages9
JournalAmerican Journal of Human Genetics
Volume90
Issue number2
DOIs
Publication statusPublished - 2012

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  • EMC OR-01-60-01

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