Chrispell Jared D, Feathers Kecia L, Kane Maureen A, Kim Chul Y, Brooks Matthew, Khanna Ritu, Kurth Ingo, Hübner Christian A, Gal Andreas, Mears Alan J, Swaroop Anand, Napoli Joseph L, Sparrow Janet R, Thompson Debra A
Departments of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
J Biol Chem. 2009 Aug 7;284(32):21468-77. doi: 10.1074/jbc.M109.020966. Epub 2009 Jun 8.
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.
RDH12突变导致早发性常染色体隐性视网膜营养不良，会使患者出现严重的视网膜病变和严重视力障碍。为了研究RDH12在视网膜中存在的视黄醇脱氢酶/还原酶（RDH）网络中的功能，我们研究了Rdh12基因缺陷小鼠的视网膜表型。在从漂白恢复过程中，Rdh12基因缺陷小鼠和野生型小鼠的全反式视黄醛还原率和11-顺式视黄醛形成率在体内相似，这两种小鼠在影响视觉循环效率的Rpe65多态性方面相互匹配。然而，Rdh12基因缺陷小鼠的视网膜匀浆在体外还原外源性视黄醛的能力明显下降。此外，在各种遗传背景的Rdh12基因缺陷小鼠中，双视黄醛化合物二视黄醛-吡啶鎓-乙醇胺（A2E）的体内水平升高。相反，视黄酸和总视黄醇的体内水平显著降低。对于Rpe65-Leu（450）多态性纯合的野生型小鼠，其Rdh12转录水平高于Rpe65-Met（450）小鼠，并且在野生型小鼠和具有全锥视网膜的Nrl基因缺陷小鼠的出生后发育过程中升高。当在对光敏感的BALB/c背景下繁殖时，或者当超氧化物歧化酶2（Sod2(+/-)）无效等位基因的杂合子时，Rdh12基因缺陷小鼠在老年时相对于野生型小鼠并未表现出视网膜变性增加。我们的研究结果表明，RDH12的关键功能是还原全反式视黄醛，其还原能力超过了光感受器外段的还原能力。
