Generation, identification and functional characterization of thenob4mutation ofGrm6in the mouse

Publisher Website
Google Scholar
Abstract
We performed genome-wide chemical mutagenesis of C57BL/6J mice usingN-ethyl-N-nitrosourea (ENU). Electroretinographic screening of the third generation offspring revealed two G3 individuals from one G1 family with a normal a-wave but lacking the b-wave that we namednob4. The mutation was transmitted with a recessive mode of inheritance and mapped to chromosome 11 in a region containing theGrm6gene, which encodes a metabotropic glutamate receptor protein, mGluR6. Sequencing confirmed a single nucleotide substitution from T to C in theGrm6gene. The mutation is predicted to result in substitution of Pro for Ser at position 185 within the extracellular, ligand-binding domain and oocytes expressing the homologous mutation in mGluR6 did not display robust glutamate-induced currents. Retinal mRNA levels forGrm6were not significantly reduced, but no immunoreactivity for mGluR6 protein was found. Histological and fundus evaluations ofnob4showed normal retinal morphology. In contrast, the mutation has severe consequences for visual function. Innob4mice, fewer retinal ganglion cells (RGCs) responded to the onset (ON) of a bright full field stimulus. When ON responses could be evoked, their onset was significantly delayed. Visual acuity and contrast sensitivity, measured with optomotor responses, were reduced under both photopic and scotopic conditions. This mutant will be useful because its phenotype is similar to that of human patients with congenital stationary night blindness and will provide a tool for understanding retinal circuitry and the role of ganglion cell encoding of visual information.