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A novel mutation in Prph2, a gene regulated by Nr2e3, causes retinal degeneration and outer-segment defects similar to Nr2e3 rd7/rd7 retinas

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Abstract

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.

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Acknowledgments

This study was supported by the Center for Biomedical Excellence Award through the National Center for Research Resources, NIH (NIH 5 P20 RRO18788-02) (NBH), the Nebraska Tobacco Settlement Biomedical Research Development (AMN, NBH), and Hope for Vision (NBH). The DNA Sequencing Core at UNMC receives partial support from the NIH (grant No. P20 RR016469) and from the INBRE Program of the National Center for Research Resources.

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Authors and Affiliations

  1. The Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198-5805, USA

    Arne M. Nystuen, Andrew J. Sachs, Yang Yuan, Laura Heuermann & Neena B. Haider

  2. Department of Ophthalmology, University of Nebraska Medical Center, Omaha, NE, 68198-5805, USA

    Neena B. Haider

  3. 6008 Durham Research Center, 985805 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, 68198-5805, USA

    Neena B. Haider

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  1. Arne M. Nystuen
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  2. Andrew J. Sachs
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  4. Laura Heuermann
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  5. Neena B. Haider
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Correspondence to Neena B. Haider.

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Nystuen, A.M., Sachs, A.J., Yuan, Y. et al. A novel mutation in Prph2, a gene regulated by Nr2e3, causes retinal degeneration and outer-segment defects similar to Nr2e3 rd7/rd7 retinas. Mamm Genome 19, 623–633 (2008). https://doi.org/10.1007/s00335-008-9138-5

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