Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene - A model for the human hereditary disease fundus albipunctatus

In the vertebrate retina, the final step of visual chromophore production i s the oxidation of 11-cis-retinol to 11-cis-retinal. This reaction is catal yzed by 11-cis-retinol dehydrogenases (11-cis-RDHs), prior to the chromopho re rejoining with the visual pigment apo-proteins. The RDH5 gene encodes a dehydrogenase that is responsible for the majority of RDH activity. In huma ns, mutations in this gene are associated with fundus albipunctatus, a dise ase expressed by delayed dark adaptation of both cones and rods. In this re port, an animal model for this disease, 11-cis-rdh-/- mice, was used to inv estigate the flow of retinoids after a bleach, and microsomal membranes fro m the retinal pigment epithelium of these mice were employed to characteriz e remaining enzymatic activities oxidizing 11-cis-retinol. Lack of 11-cis-R DH leads to an accumulation of cis-retinoids, particularly 13-cis-isomers. The analysis of 11-cis-rdh-/- mice showed that the RDH(s) responsible for t he production of 11-cis-retinal displays NADP-dependent specificity toward 9-cis- and 11-cis-retinal but not 13-cis-retinal. The lack of 13-cis-RDH ac tivity could be a reason why 13-cis-isomers accumulate in the retinal pigme nt epithelium of 11-cis-rdh-/- mice. Furthermore, our results provide detai led characterization of a mouse model for the human disease fundus albipunc tatus and emphasize the importance of 11-cis-RDH in keeping the balance bet ween different components of the retinoid cycle.