期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 90, 期 2, 页码 331-339出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2011.12.006
关键词
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资金
- National Institutes of Health [R21EY021852, R01EY12354, R01EY014701, RR017890, R01EY016501, P30CA34196, R01EY004864, P30EY006360, R01NS43459, R01EY020821]
- Veterans Administration Medical Research Service
- Netherlands Organization for Scientific Research (Zon-MW NWO)
- ODAS
- European Commission [RETICIRC HEALTH-F2-2009-223156]
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Foundation Fighting Blindness Canada
- Canadian Institutes for Health Research
- Reseau Vision
- Fonds de recherche du Quebec-Sante
- Foundation Fighting Blindness Center
- Research to Prevent Blindness
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.
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