Mutations in the GRM6 Gene Encoding the Mglur6 Receptor in Patients With Autosomal Recessive Night Blindness and Abnormal Cone ERG on Responses

Abstract

Abstract: : Purpose: ON–bipolar cells use the metabotropic glutamate receptor mGluR6 to detect the neurotransmitter glutamate released by the rods and cones. Mice lacking the grm6 gene encoding the mGluR6 receptor (Masu et al. Cell 80:757–765, 1995) have a defect in their ON–bipolar cell responses to light, but it is still unclear how their subjective visual function is affected. We undertook this study to search for patients with the homologous genotype and to characterize their visual function. Methods: We sequenced the DNA corresponding to the 10 exons of the GRM6 gene in 26 patients with a prior diagnosis of congenital stationary night blindness. Ophthalmic evaluations included full–field flash electroretinography (ERG). Sawtooth stimuli were used to elicit cone ERG ON and OFF responses. Results: Three of the 26 patients had allelic sequence variations of the GRM6 gene which we interpreted as pathogenic, loss–of–function mutations. One patient was homozygous for the nonsense mutation Arg621End. A second patient was a compound heterozygote with the nonsense mutation Gln708End and the missense mutation Glu150Ser. The third patient was homozygous for the missense change Glu781Lys. The missense mutations Glu150Ser and Glu781Lys alter highly conserved residues. Rod ERG responses to single dim light flashes were non–detectable. Rod–plus–cone ERG responses to single bright white light flashes showed a cornea–negative ERG with low normal to subnormal a–waves and severely reduced b–waves. Sawtooth–stimuli cone ERGs showed markedly reduced ON responses and normal OFF responses. Conclusions: Null mutations of the GRM6 gene cause a novel form of autosomal recessive congenital night blindness associated with a negative rod ERG and defective cone ERG ON response.

Keywords: bipolar cells • neurotransmitters/neurotransmitter systems • mutations