AbstractElectroretinogram (ERG) studies identified a new mouse line with a normal a-wave
but lacking the b-wave component. The ERG phenotype of this new allele,
nob7, matched closely that of mouse mutants for
Grm6, Lrit3, Trpm1, and
Nyx, which encode for proteins expressed in depolarizing
bipolar cells (DBCs). To identify the underlying mutation, we first crossed
nob7 mice with Grm6nob3 mutants and measured the ERGs in offspring. All the offspring lacked the
b-wave, indicating that nob7 is a new allele for
Grm6: Grm6nob7. Sequence analyses of Grm6nob7 cDNAs identified a 28 base pair insertion between exons 8 and 9, which
would result in a frameshift mutation in the open reading frame that encodes the
metabotropic glutamate receptor 6 (Grm6). Sequencing both the
cDNA and genomic DNA from exon 8 and intron 8, respectively, from the
Grm6nob7 mouse revealed a G to A transition at the last position in exon 8. This
mutation disrupts splicing and the normal exon 8 is extended by 28 base pairs,
because splicing occurs 28 base pairs downstream at a cryptic splice donor.
Consistent with the impact of the resulting frameshift mutation, there is a loss
of mGluR6 protein (encoded by Grm6) from the dendritic tips of
DBCs in the Grm6nob7 retina. These results indicate that Grm6nob7 is a new model of the complete form of congenital stationary night
blindness, a human condition that has been linked to mutations of
GRM6.
Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness
