GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night 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 b-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.
Cole Eye Institute, Cleveland Clinic, OH 44195, USA.
Neal S
NS
Peachey
Thomas A
TA
Ray
Ralph
R
Florijn
Lucy B
LB
Rowe
Trijntje
T
Sjoerdsma
Susana
S
Contreras-Alcantara
Kenkichi
K
Baba
Gianluca
G
Tosini
Nikita
N
Pozdeyev
P Michael
PM
Iuvone
Pasano
P
Bojang
Jillian N
JN
Pearring
Huibert Jan
HJ
Simonsz
Maria
M
van Genderen
David G
DG
Birch
Elias I
EI
Traboulsi
Allison
A
Dorfman
Irma
I
Lopez
Huanan
H
Ren
Andrew F X
AF
Goldberg
Patsy M
PM
Nishina
Pierre
P
Lachapelle
Maureen A
MA
McCall
Robert K
RK
Koenekoop
Arthur A B
AA
Bergen
Maarten
M
Kamermans
Ronald G
RG
Gregg
D000818:Animals; D002874:Chromosome Mapping / Q000379:methods; D003623:Dark Adaptation / Q000235:genetics; D004596:Electroretinography / Q000379:methods; D015785:Eye Diseases, Hereditary; D055785:Gene Knockdown Techniques / Q000379:methods; D040181:Genetic Diseases, X-Linked; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D009216:Myopia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D009755:Night Blindness / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D051245:Retinal Bipolar Cells / Q000378:metabolism* / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D015027:Zebrafish
D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; C113897:metabotropic glutamate receptor 6