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.
Chrispell
Jared D
JD
Departments of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
Feathers
Kecia L
KL
Kane
Maureen A
MA
Kim
Chul Y
CY
Brooks
Matthew
M
Khanna
Ritu
R
Kurth
Ingo
I
Hübner
Christian A
CA
Gal
Andreas
A
Mears
Alan J
AJ
Swaroop
Anand
A
Napoli
Joseph L
JL
Sparrow
Janet R
JR
Thompson
Debra A
DA
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
D012176:Retinoids; D000429:Alcohol Oxidoreductases; C517812:Rdh12 protein, mouse; D013482:Superoxide Dismutase; D050697:Retinal Dehydrogenase