Targeted Disruption of the Murine Retinal Dehydrogenase Gene Rdh12 Does Not Limit Visual Cycle Function

Abstract

RDH12 codes for a member of the family of short-chain alcohol dehydrogenases/reductases proposed to function in the visual cycle that supplies the chromophore 11-cis retinal to photoreceptor cells. Mutations in RDH12 cause severe and progressive childhood onset autosomal-recessive retinal dystrophy, including Leber congenital amaurosis. We generated Rdh12 knockout mice, which exhibited grossly normal retinal histology at 10 months of age. Levels of all-trans and 11-cis retinoids in dark- and light-adapted animals and scotopic and photopic electroretinogram (ERG) responses were similar to those for the wild type, as was recovery of the ERG response following bleaching, for animals matched for an Rpe65 polymorphism (p.L450M). Lipid peroxidation products and other measures of oxidative stress did not appear to be elevated in Rdh12^−/− animals. RDH12 was localized to photoreceptor inner segments and the outer nuclear layer in both mouse and human retinas by immunohistochemistry. The present findings, together with those of earlier studies showing only minor functional deficits in mice deficient for Rdh5, Rdh8, or Rdh11, suggest that the activity of any one isoform is not rate limiting in the visual response.

Grant support for this study was given by the Deutsche Forschungsgemeinschaft (I.K. and C.A.H. [SFB444 and FG604]), EV-GENORET (LSHG-CT-2005-512036) (A.G.), the National Institutes of Health (R01-EY12298, P30-EY07003, M01-RR00042, and P60DK-20572), the Foundation for Fighting Blindness, and Research to Prevent Blindness (D.A.T.).

Gifts of antibodies were given by the following people: anti-rhodopsin, Barry E. Knox at SUNY Upstate; anti-prRDH antibodies, Amir Rattner and Jeremy Nathans at Johns Hopkins University; anti-RDH5, Kryzsztof Palczewski at Case Western Reserve University; anti-LRAT, Dean Bok at University of California-Los Angeles; anti-CRALBP, John Crabb at Cleveland Clinic; and anti-NRL, Anand Swaroop at University of Michigan. Technical support was given by Irm Hermans-Borgmeyer and Antje K. Hübner (Rdh12^−/− mice); by Mitchell Gillett (morphology); by Elizabeth Smith (hybridomas); by Ali Derin, Susanne Conrad, and Austra Liepa (animal care); and by Naheed Khan (electrophysiology).