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 is the oxidation of 11-cis-retinol to 11-cis-retinal. This reaction is catalyzed by 11-cis-retinol dehydrogenases (11-cis-RDHs), prior to the chromophore rejoining with the visual pigment apo-proteins. The RDH5 gene encodes a dehydrogenase that is responsible for the majority of RDH activity. In humans, mutations in this gene are associated with fundus albipunctatus, a disease expressed by delayed dark adaptation of both cones and rods. In this report, an animal model for this disease, 11-cis-rdh-/- mice, was used to investigate the flow of retinoids after a bleach, and microsomal membranes from the retinal pigment epithelium of these mice were employed to characterize remaining enzymatic activities oxidizing 11-cis-retinol. Lack of 11-cis-RDH 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 the 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 activity could be a reason why 13-cis-isomers accumulate in the retinal pigment epithelium of 11-cis-rdh-/- mice. Furthermore, our results provide detailed characterization of a mouse model for the human disease fundus albipunctatus and emphasize the importance of 11-cis-RDH in keeping the balance between different components of the retinoid cycle.
Jang
G F
GF
Department of Ophthalmology, University of Washington, Seattle, Washington 98195, USA.
Van Hooser
J P
JP
Kuksa
V
V
McBee
J K
JK
He
Y G
YG
Janssen
J J
JJ
Driessen
C A
CA
Palczewski
K
K
D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002678:Chimera; D003433:Crosses, Genetic; D003624:Darkness; D005260:Female; D005838:Genotype; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000201:enzymology*; D012176:Retinoids / Q000302:isolation & purification / Q000378:metabolism; D013379:Substrate Specificity; D014801:Vitamin A / Q000378:metabolism*
D012176:Retinoids; D014801:Vitamin A; D019308:Palmitic Acid; D000429:Alcohol Oxidoreductases; C022520:retinol dehydrogenase