Allelic variance between GRM6 mutants, Grm6^nob3 and Grm6^nob4 results in differences in retinal ganglion cell visual responses

Abstract

An electroretinogram (ERG) screen identified a mouse with a normal a-wave but lacking a b-wave, and as such it was designated no b-wave3 (nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene (Grm6 RGCs. Grm6nob4/nob3 RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6 nob3 is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6 nob3 and Grm6 nob4 creates a disparity in inner retinal processing. Because the localization of GRM6 is limited to bipolar cells in the On pathway, the observed difference between RGCs in these mutants is likely to arise from differences in their inputs.

Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms

“…The overall phenotype is in accordance with the phenotype of the nob mice and patients with cCSNB described above indicating a dysfunction of ON-bipolar cell signalling. Furthermore, significant visual dysfunction occur in all Grm6 mutant mice (Iwakabe et al, 1997;Maddox et al, 2008;Takao et al, 2000), similar to the human cCSNB phenotype (Dryja et al, 2005;O'Connor et al, 2006;Zeitz et al, 2005b). However, neither the mutant mice nor the patients are completely blind under scotopic or photopic conditions, indicating that there are compensating mechanisms that underlie the differences in retinal output and visual behaviour (Maddox et al, 2008).…”

“…Mouse models for GRM6 gene defect. Three mouse models have been described for GRM6: One laboratory-generated complete knockout (Grm6 tm1Nak ) (Masu et al, 1995), a naturally occurring mouse (nob3) carrying a mutation in intron 2, which leads to a novel splice site with a larger transcript: c.486þ648C>T, r.486_487þ486ins582_6446, which is predicted to truncate the protein (p.Ile163Glyfs*103) (Maddox et al, 2008) and a chemically induced mouse model (nob4) harbouring a missense mutation in exon 3 (c.553T>C; p.Ser185Pro) (Maddox et al, 2008;Pinto et al, 2007) (Table 4). Clinically, the three mouse lines resemble each other in that they all lack the scotopic and photopic b-wave, while the a-waves are well preserved.…”

Constructing the rod bipolar cell signalplex using animal models of retinal dysfunction.

“…The gating mechanism of Gβγ on the TRPM1 channel will be important to [10][11][12][13][14][15][16][18][19][20] In this report, we define a critical role for GPR179, a previously uncharacterized orphan G protein receptor, in the DBC signal transduction cascade and in human cCSNB. Specifically, mutations in GPR179 in humans are responsible for a form of cCSNB.…”

Light-Evoked Responses of the Retinal Pigment Epithelium: Changes Accompanying Photoreceptor Loss in the Mouse

“…In the present study, we used a genetic approach to isolate slow PIII. For mouse-based studies focused on the outer retina, crossing the mutation of interest to Nyx nob , or another mouse model that lacks the ERG b-wave such as Grm6 nob3 (Maddox et al 2008;Masu et al 1995) (Morgans et al 2009), will allow slow PIII to be measured. In this study, we used Nyx nob to unmask slow PIII and were able to demonstrate that it was relatively conserved compared with a-wave amplitude in Prph Rd2/ϩ mutants.…”