title: Rdh12 activity and effects on retinoid processing in the murine retina.
abstract: 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.
authors.affiliation: Departments of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
authors.forename: Jared D
authors.initials: JD
authors.lastname: Chrispell
authors.forename: Kecia L
authors.initials: KL
authors.lastname: Feathers
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.forename: Chul Y
authors.initials: CY
authors.lastname: Kim
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.forename: Ritu
authors.initials: R
authors.lastname: Khanna
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mears
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.forename: Janet R
authors.initials: JR
authors.lastname: Sparrow
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D006579:Heterozygote; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D011110:Polymorphism, Genetic; D012160:Retina / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D012176:Retinoids; D000429:Alcohol Oxidoreductases; C517812:Rdh12 protein, mouse; D013482:Superoxide Dismutase; D050697:Retinal Dehydrogenase