Characterization of a dominant cone degeneration in a green fluorescent protein-reporter mouse with disruption of loci associated with human dominant retinal dystrophy

Purpose. To characterize anatomically and functionally the retinal degeneration observed in a transgenic mouse line (OPN1LW-EGFP) expressing enhanced green fluorescent protein (EGFP) in a subpopulation of cone photoreceptors, and to map the location of the transgenic insertion. Methods. An anatomic comparison of cone survival was carried out between wild type (WT) and transgenic mice at three postnatal time points (P80, P140, and P245). Retinal function was assessed at P245 by ERG and included an ultraviolet flicker stimulus to isolate S-cone function. Chromosomal mapping by FISH and high-resolution mapping on DNA fibers (Fiber-FISH) were performed to identify the location of the transgenic insertion. Results. GFP expression was largely absent in S-cones. Cone numbers were significantly reduced in OPN1LW-EGFP mice at all time points compared to WT, with cone loss independent of GFP expression. Anatomic loss correlated with a functional deficit in dark- and light-adapted ERG responses, including a reduction in UV-flicker response, confirming the degeneration of S-cones. The phenotype of heterozygote mice was slightly less severe than in homozygotes, consistent with a dominantly inherited cone dystrophy. The transgenic insertion mapped to a specific region on chromosome 10 orthologous with loci for progressive bifocal chorioretinal atrophy and North Carolina macular dystrophy on human chromosome 6. Conclusions. Cone loss is global in OPN1LW-EGFP mice and is independent of GFP expression. The mechanism underlying the degeneration remains elusive; however, disruption of loci associated with dominantly inherited retinal degenerations in humans makes this mouse of great interest.