Mapping of genetic modifiers of Nr2e3 rd7/rd7 that suppress retinal degeneration and restore blue cone cells to normal quantity

The retinal degeneration 7 (rd7) mouse, lacking expression of the Nr2e3 gene, exhibits retinal dysplasia and a slow, progressive degeneration due to an abnormal production of blue opsin-expressing cone cells. In this study we evaluated three strains of mice to identify alleles that would slow or ameliorate the retinal degeneration observed in Nr2e3 ^rd7/rd7 mice. Our studies reveal that genetic background greatly influences the expression of the Nr2e3 ^rd7/rd7 phenotype and that the inbred mouse strains CAST/EiJ, AKR/J, and NOD.NON-H2 ^nb1 carry alleles that confer resistance to Nr2e3 ^rd7/rd7 -induced retinal degeneration. B6.Cg-Nr2e3 ^rd7/rd7 mice were outcrossed to each strain and the F₁ progeny were intercrossed to produce F₂ mice. In each intercross, 20–24% of the total F₂ progeny were homozygous for the Nr2e3 ^rd7/rd7 mutation in a mixed genetic background; approximately 28–48% of the Nr2e3 ^rd7/rd7 homozygotes were suppressed for the degenerative retina phenotype in a mixed genetic background. The suppressed mice had no retinal spots and normal retinal morphology with a normal complement of blue opsin-expressing cone cells. An initial genome scan revealed a significant association of the suppressed phenotype with loci on chromosomes 8 and 19 with the CAST/EiJ background, two marginal loci on chromosomes 7 and 11 with the AKR/J background, and no significant QTL with the NOD.NON-H2 ^nb1 background. We did not observe any significant epistatic effects in this study. Our results suggest that there are several genes that are likely to act in the same or parallel pathway as NR2E3 that can rescue the Nr2e3 ^rd7/rd7 phenotype and may serve as potential therapeutic targets. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.