Severe Retinal Degeneration Caused by a Novel Rhodopsin Mutation

Rhodopsin gene (Rho) mutations are one of the most prevalent causes of retinitis pigmentosa (RP). More than 100 predominantly autosomal dominant RHO mutations have been reported to cause RP in humans (http://www.sph.uth.tmc.edu/RetNet/home.htm). The phenotypic expression, disease progression, and vision impairment are often variable among patients carrying identical or different rhodopsin mutations. To examine the mechanisms linking mutations in Rho to the death of photoreceptor cells, transgenic mice expressing rhodopsin mutations as found in patients with RP and knockout mice lacking rhodopsin have been generated.1–5 Rhodopsin knockout mice display clear, reproducible differences in the time course of photoreceptor cell degeneration in comparison with transgenic rodent models expressing mutant rhodopsin. Studies of these animal models provide valuable insight into the roles of rhodopsin in the structure of rod photoreceptor outer segments, in the phototransduction pathway, and in the pathogenesis of mutant rhodopsin proteins causing rod photoreceptor cell death.6–11 Specific stress signaling pathways mediating the unfolded protein response have been reported to be responsible for the pathologic events triggered by misfolded rhodopsin mutant proteins.12 Experimental therapeutic approaches designed to inhibit the activation of stress signals triggered by unfolded protein response or to prevent the production of either mutant proteins or transcripts show some efficacy in animal models for slowing the progression of vision loss.13–17 Given that there are more than 100 identified mutations in human RP, a comprehensive picture of how different rhodopsin mutations induce various photoreceptor cell degeneration pathways is far from complete.18 Therefore, further studies are needed to investigate the mechanisms for why and how patients with identical or different rhodopsin mutations display a wide range of phenotypic variability. New animal models that recapitulate similar rhodopsin mutations found in human patients with RP will be useful for mechanistic studies and for testing or developing new therapeutic approaches. We have identified a new mouse mutation that displays dominant retinal degeneration (RD) from a screen of N-ethyl-N-nitrosourea (ENU)-mutagenized mice. We have further determined that this severe RD phenotype is caused by a point mutation of the rhodopsin gene resulting in a mutated Rho-C185R protein. Our studies suggest that this mouse rhodopsin mutant line is a useful model for understanding how rhodopsin mutant proteins trigger the death of rod photoreceptors.