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

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 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.

Functional and structural impact of the loss of the leucine-rich repeat protein LRIT1 in the mouse retina.

“…This is caused by absence of a functional ON bipolar cell signaling cascade resulting in defective post-synaptic responses. The known modes of inheritance for cCSNB are x-linked (Nyx) and autosomal recessive (Grm6, Trpm1, Gpr179, Lrit3) (25, [30][31][32]63,[70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87].…”

Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

“…Binding of glutamate to mGluR6 activates the Gαo g-protein mediated cascade. The activation of Gαo results in the closure of the ion channel, TRPM1 (Dhingra et al, 2000;Sampath and Rieke, 2004;Snellman et al, 2008;Bellone et al, 2008;Shen et al, 2009;Morgans et al, 2009;van Genderen et al, 2009Peachey et al, 2012). In response to light, the photoreceptors hyperpolarize and reduce glutamate release and the subsequent activation of mGluR6.…”

“…Mouse strains used in the investigation of the function and expression of LRIT3 in the retina (chapter V) include the Nyx nob and TrpM1 -/-mice which have been described previously (Cao et al, 2012;Masu et al, 1995;Pardue, et al, 1998;Peachey et al, 2012;Pearring et al, 2011). Trpm1 -/-(Trpm1 tm1Lex ) mice were originally generated by Lexicon Genetics and can be obtained from the European Mouse Mutant Archive (emmanet.org).…”

“…In the dark, glutamate is continuously released from rod and cone photoreceptors and binds to the mGluR6 receptors on the post-synaptic ON BC dendrites (Nakajima et al, 1993;Nomura et al, 1994). Once bound, a Go gprotein coupled cascade is activated (Nawy et al, 1999;Dhingra et al, 2000Dhingra et al, , 2002Dhingra et al, , 2012, which, through several intervening steps that have yet to be fully elucidated, closes the TRPM1 cation channel (Morgans et al, 2009;Shen et al, 2009;Koike et al, 2010;Peachey et al 2012). In response to light, glutamate release is decreased and mGluR6 is inactivated.…”

“…A few studies have looked at the localization of TRPV1 in the retina using antibodies, but results vary and although it is clear that TRPV1 mRNA and protein are present in the retina the specific cell types that express the TRPV1 remain unknown (Gilliam & Wensel, 2011). In goldfish, TRPV1-like channels are Mouse strains used in the investigation of the function and expression of LRIT3 in the retina (chapter V) include the Nyx nob and TrpM1 -/-mice which have been described previously (Cao et al, 2012;Masu et al, 1995;Pardue, et al, 1998;Peachey et al, 2012;Pearring et al, 2011). …”