segments ( 1 ). The lipid phase of the disc membrane is dominated by phospholipids (87 mol % of total lipid in human outer segment membrane) with the major species being phosphatidylcholine (PC) (32.5 mol %), phosphatidylethanolamine (PE) (37.6 mol %), and phosphatidylserine (PS) (12.1 mol %) ( 2 ). A remarkable feature of the phospholipids of the outer segment disc membrane is their unusually high content of long-chain polyunsaturated (e.g., 22:6 n -3) fatty acids; in human outer segments, 22:6 n -3 accounts for 34.2% of the fatty acid in PE, 19.5% of the fatty acid in PC and 34.1% of the fatty acid in PC ( 2 ). Indeed, docosahexaenoic acid (DHA) is more abundant in photoreceptor outer segments that in any other mammalian cell membrane ( 2 ). These unsaturated acyl chains provide the high fl uidity necessary for proper signal transduction in the disc membrane.Following absorption of a photon, the 11-cis -retinal chromophore of visual pigment rhodopsin isomerizes to all-trans -retinal and initiates a series of conformational rearrangements leading to formation of metarhodopsin II, a 380-nm absorbing species that consists of all-trans -retinal bound to opsin by a deprotonated Schiff base linkage ( Fig. 1 ). Metarhodopsin II is distinguished by its ability to activate the G protein transducin ( 3 ). This activation initiates the phototransduction cascade leading to hyperpolarization of the photoreceptor cell and altered neurotransmitter release. Movement of phospholipid species during the rhodopsin to metarhodopsin II transition has been reported by multiple groups ( 4, 5 ). PHOSPHOLIPID ASSOCIATIONS WITH RHODOPSINThroughout the outer segment compartment of the photoreceptor cell, visual pigments (rhodopsin in rods and cone pigments) are densely packed within the plasma membrane and disc membranes; low levels of rhodopsin are also present in the plasma membrane of the rod inner
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 alltrans-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 lightsensitive 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 is a major disease gene for Leber congenital amaurosis, with RDH12 mutations responsible for approximately 2% of cases of childhood-onset severe autosomal recessive retinal dystrophy (1-4). Affected individuals experience poor vision in early life, which progressively declines with age as a result of both rod and cone degeneration (5). Analyses of retinal organization and visual function in patients with mutations in RDH12 or RPE65, another Leber congenital amaurosis gene involved in retinoid metabolism, show distinctly different pathologies associated with defects in each gene that will be important to consider when developing targeted forms of therapy (6).RDH12 encodes a member of the family of short chain dehydrogenases/reductases that catalyze oxidation and reduction reactions involved in various aspects of metabolism (reviewed in Refs. 7 and 8). In the photoreceptor cells and retinal pigment epithelium (RPE), 3 the interconversion of oxidized and reduced retinoids by RDH enzymes is an important feature of the visual cycle, the process responsible for the conversion of vitamin A (all-trans-retinol) to 11-cis-retinal, the chromophore of the visual pigments (reviewed in Ref. 9). On the basis of in vitro assays showing reactivity toward retinaldehyde substrates and expression in photoreceptor cells, RDH12 was initially proposed to function in the reduction of all-trans-retinal released by bleached visual pigments (10...
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