Abstract
Mutation of RPE65 can cause severe blindness from birth or early childhood, and RPE65 protein is associated with retinal pigment epithelium (RPE) vitamin A metabolism. Here, we show that Rpe65-deficient mice exhibit changes in retinal physiology and biochemistry. Outer segment discs of rod photoreceptors in Rpe65–/– mice are disorganized compared with those of Rpe65+/+ and Rpe65+/– mice. Rod function, as measured by electroretinography, is abolished in Rpe65–/– mice, although cone function remains. Rpe65–/– mice lack rhodopsin, but not opsin apoprotein. Furthermore, all-trans-retinyl esters over-accumulate in the RPE of Rpe65–/– mice, whereas 11-cis-retinyl esters are absent. Disruption of the RPE-based metabolism of all-trans-retinyl esters to 11-cis-retinal thus appears to underlie the Rpe65-/- phenotype, although cone pigment regeneration may be dependent on a separate pathway.
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Acknowledgements
We acknowledge the technical support of M. Lloyd, M. Kvaas and A. Van Dyke. We wish to thank S. Gentleman and G. Nuckolls for critical reading of the manuscript and for valuable suggestions. This research was supported in part by NIH grants EY00331 (D.B.), EY00444 (D.B.), EY12231 (J.X.M.) and EY04939 (R.K.C.) and by the Foundation Fighting Blindness (UCLA and MUSC). D.B. is a Research to Prevent Blindness Senior Scientific Investigator and Dolly Green Professor of Ophthalmology at UCLA.
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Redmond., T., Yu, S., Lee, E. et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20, 344–351 (1998). https://doi.org/10.1038/3813
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DOI: https://doi.org/10.1038/3813
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