A novel mutation in Prph2, a gene regulated by Nr2e3, causes retinal degeneration and outer-segment defects similar...

The nmf193 mutant was generated by a large-scale ENU mutagenesis screen and originally described as having a dominantly inherited phenotype characterized by fundus abnormalities. We determined that nmf193 mice exhibit outer-segment defects and progressive retinal degeneration. Clinical examination revealed retinal spotting apparent at 6 weeks of age. Histologic analysis of homozygous mutant mice at 6 weeks indicated an absence of outer segments (OS) and a 50% reduction of photoreceptor cells which progressed to complete loss of photoreceptors by 10 months. Mice heterozygous for the nmf193 mutation had a less severe phenotype of shortened outer segments at 2 months with progressive loss of photoreceptor cells to 50% by 10 months. A positional cloning approach using a DNA pooling strategy was performed to identify the causative mutation in nmf193 mice. The nmf193 mutation was linked to chromosome 17 and fine mapped to an interval containing the peripherin/rds (Prph2) gene. Mutation analysis identified a single base change in Prph2 that causes aberrant splicing between exons 1 and 2. Interestingly, a comparative histologic analysis demonstrated that Prph2 ( nmf193/+ ) mutants have similar photoreceptor degeneration to that of Nr2e3 ( rd7/rd7 ). We show that Prph2 mRNA and protein levels are reduced in the Nr2e3 ( rd7/rd7 ) mutant compared to control littermates. Chromatin immunoprecipitation analysis shows that Prph2 is a direct target of NR2E3. In addition, the downregulation of Prph2 gene expression is similar in both the Nr2e3 ( rd7/rd7 ) and Prph2 ( nmf193/+ ) mutants, suggesting that the reduction of Prph2 may contribute to the degenerative pathology seen in Nr2e3 ( rd7/rd7 ).