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 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.