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J Neurophysiol. 2017 Aug 1;118(2):845-854. doi: 10.1152/jn.00888.2016. Epub 2017 May 10.

A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function.

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Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio.
Department of Ophthalmology, Cleveland Clinic College of Medicine of Case Western Reserve University, Cleveland, Ohio.
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky.
The Jackson Laboratory, Bar Harbor, Maine.
Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; and.
Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky.
The Jackson Laboratory, Bar Harbor, Maine;


GRM6 encodes the metabotropic glutamate receptor 6 (mGluR6) used by retinal depolarizing bipolar cells (DBCs). Mutations in GRM6 lead to DBC dysfunction and underlie the human condition autosomal recessive complete congenital stationary night blindness. Mouse mutants for Grm6 are important models for this condition. Here we report a new Grm6 mutant, identified in an electroretinogram (ERG) screen of mice maintained at The Jackson Laboratory. The Grm6nob8 mouse has a reduced-amplitude b-wave component of the ERG, which reflects light-evoked DBC activity. Sequencing identified a missense mutation that converts a highly conserved methionine within the ligand binding domain to leucine (p.Met66Leu). Consistent with prior studies of Grm6 mutant mice, the laminar size and structure in the Grm6nob8 retina were comparable to control. The Grm6nob8 phenotype is distinguished from other Grm6 mutants that carry a null allele by a reduced but not absent ERG b-wave, decreased but present expression of mGluR6 at DBC dendritic tips, and mislocalization of mGluR6 to DBC somas. Consistent with a reduced but not absent b-wave, there were a subset of retinal ganglion cells whose responses to light onset have times to peak within the range of those in control retinas. These data indicate that the p.Met66Leu mutant mGluR6 is trafficked less than control. However, the mGluR6 that is localized to the DBC dendritic tips is able to initiate DBC signal transduction. The Grm6nob8 mouse extends the Grm6 allelic series and will be useful for elucidating the role of mGluR6 in DBC signal transduction and in human disease.NEW & NOTEWORTHY This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a distinct phenotype from that seen in other Grm6 mouse models.


bipolar cell; electroretinogram; ganglion cell; retina; retinal disease

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