Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

RDH12 mutations are responsible for early-onset autosomal recessive retinal dystrophy, which results in profound retinal pathology and severe visual handicap in patients. To investigate the function of RDH12 within the network of retinoid dehydrogenases/reductases (RDHs) present in retina, we studied the retinal phenotype of Rdh12-deficient mice. In vivo rates of all-trans-retinal reduction and 11-cis-retinal formation during recovery from bleaching were similar in Rdh12-deficient and wild-type mice matched for an Rpe65 polymorphism that impacts visual cycle efficiency. However, retinal homogenates from Rdh12-deficient mice exhibited markedly decreased capacity to reduce exogenous retinaldehydes in vitro. Furthermore, in vivo levels of the bisretinoid compound diretinoid-pyridinium-ethanolamine (A2E) were increased in Rdh12-deficient mice of various genetic backgrounds. Conversely, in vivo levels of retinoic acid and total retinol were significantly decreased. Rdh12 transcript levels in wild-type mice homozygous for the Rpe65-Leu(450) polymorphism were greater than in Rpe65-Met(450) mice and increased during postnatal development in wild-type mice and Nrl-deficient mice having an all-cone retina. Rdh12-deficient mice did not exhibit increased retinal degeneration relative to wild-type mice at advanced ages, when bred on the light-sensitive BALB/c background, or when heterozygous for a null allele of superoxide dismutase 2 (Sod2(+/-)). Our findings suggest that a critical function of RDH12 is the reduction of all-trans-retinal that exceeds the reductive capacity of the photoreceptor outer segments.This work was supported, in whole or in part, by National Institutes of Health Grants P30-EY07003 (Michigan Vision Core Grant) and P60-DK-20572 (Michigan Diabetes Research and Training Center). EY11115 (to A. S.), AG13566 (to J. L. N.), and EY12951 (to J. R. S.). This work was also supported by Functional Genomics of the Retina in Health and Disease (EVI-GENORET) Grant LSHG-CT-2005-512036 (to A. G.), the Foundation Fighting Blindness (to D. A. T. and A. S.), Research to Prevent Blindness (to D. A. T. and A. S.), Midwest Eye Banks (to J. D. C.), and the Kaplan Foundation (to J. R. S.)