RDH12 Activity and Effects on Retinoid Processing in the Murine Retina.

RDH12 mutations are responsible for early-onset autosomal recessive retinal dystrophy that 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 are studying the retinal phenotype of Rdh12-deficient mice. Rates of all-trans retinol 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 A2E were increased in Rdh12-deficient mice on 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-Leu450 polymorphism were greater than in Rpe65-Met450 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, or 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.