RPE65 IS NECESSARY FOR PRODUCTION OF 11-CIS-VITAMIN A IN THE RETINAL VISUAL CYCLE

Mutation of RPE65 can cause severe blindness from birth or early child hood, and RPE65 protein is associated with retinal pigment epithelium (RPE) vitamin A metabolism. Here. we show that Rpe65-deficient mice ex hibit changes in retinal physiology and biochemistry. Outer segment di scs of rod photoreceptors in Rpe65(-/-) mice are disorganized compared with those of Rpe65(+/+) and Rpe65(+/-) mice. Rod function, as measur ed by electroretinography, is abolished in Rpe65(-/-) mice, although c one function remains. Rpe65(-/-) mice lack rhodopsin, but not opsin ap oprotein. Furthermore, all-trans-retinyl esters over-accumulate in the RPE of Rpe65(-/-) mice, whereas 11-cis-retinyl esters are absent. Dis ruption of the RPE-based metabolism of all-trans-retinyl esters to 11- cis-retinal thus appears to underlie the Rpe65(-/-) phenotype, althoug h cone pigment regeneration may be dependent on a separate pathway.