Primary Structure of Human 11-cisRetinol Dehydrogenase and Organization and Chromosomal Localization of the Corresponding Gene

Simon, András; Lagercrantz, Jacob; Bajalica‐Lagercrantz, Svetlana; Eriksson, Ulf

doi:10.1006/geno.1996.0487

Cited by 62 publications

(44 citation statements)

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“…Human Rdh5 gene mutations (35) cause fundus albipunctatus, a retinal dystrophy with markedly delayed recovery of visual sensitivity after bleaching light exposure (5,36). Both 11-cis retinol and 11-cis-retinyl esters accumulate in mice lacking Rdh5.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the visual cycle in vivo by 13 -cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Sieving

Chaudhry

Kondo

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

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As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration.vitamin A ͉ rhodopsin ͉ rat ͉ electroretinogram ͉ rod photoreceptor V isual response in vertebrate rod photoreceptors begins when light isomerizes the rhodopsin chromophore 11-cis retinal to all-trans retinal. The bleached photopigment activates the signal transduction cascade within the rod, leading to membrane hyperpolarization and thereby to retinal visual signaling. Part of the recovery mechanism from bleach requires reconversion of the chromophore to 11-cis retinal by enzymatic reactions (the vitamin A cycle) that occur within the adjacent retinal pigment epithelium (RPE) (1). Disruption of the vitamin A cycle retards restoration of night vision sensitivity. Human dietary vitamin A deficiency can cause night blindness (2), as does dietary substitution of retinoic acid in rats (3). Alternatively, night blindness can result from death and loss of rod photoreceptors in retinal degeneration (4), including some forms involving mutations in genes necessary for retinoid processing in the RPE (5). Some isotretinoin patients report impaired visual sensitivity at night and daytime glare sensitivity, suggesting photoreceptor compromise or loss (6). We have investigated the mechanism of isotretinoin-induced night blindness by evaluating ERGs, rates of rhodopsin regeneration, and retinoid processing in rats. We also evaluated the possible therapeutic benefit of isotretinoin in the rat light-damage model of retinal degeneration. Materials and MethodsAnimals. Protocols were approved by the University of Michigan's Committee on the Use and Care of Animals. SpragueDawley male 7-wk-old albino rats (Charles River Breeding Laboratories) were housed in 12:12 h light͞dark cycle of 5 lux fluorescent white light. Rats were fed high-fat breeding chow (Formulab; PMI Feeds, St. Lou...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the visual cycle in vivo by 13 -cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Sieving

Chaudhry

Kondo

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Construction of RDH5 Mutants-Human RDH5 cDNA (14) was subcloned into the eukaryotic expression vector pSG5 (15), and the expression vectors for mutant enzymes were generated by single-stranded mutagenesis (16,17). Mutants S73F and G238W were generated as described previously (2).…”

Section: Methodsmentioning

confidence: 99%

Biochemical Defects in 11-cis-Retinol Dehydrogenase Mutants Associated with Fundus Albipunctatus

Lidén

Romert

Tryggvason

et al. 2001

Journal of Biological Chemistry

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Mutations in the gene encoding 11-cis-retinol dehydrogenase (RDH5; EC 1.1.1.105) are associated with fundus albipunctatus, an autosomal recessive eye disease characterized by stationary night blindness and accumulation of white spots in the retina. In addition, some mutated alleles are associated with development of cone dystrophy, especially in elderly patients. The numbers of identified RDH5 mutations linked to fundus albipunctatus have increased considerably during recent years. In this work, we have characterized the biochemical and cell biological properties of 11 mutants of RDH5 to understand the molecular pathology of the disease. All RDH5 mutants showed decreased protein stability and subcellular mislocalization and, in most cases, loss of enzymatic activity in vitro and in vivo. Surprisingly, mutant A294P displays significant enzymatic activity. Cross-linking studies and molecular modeling showed that RDH5 is dimeric, and co-expression analyses of wild-type and mutated alleles showed that the mutated enzymes, in a transdominant-negative manner, influenced the in vivo enzymatic properties of functional variants of the enzyme, particularly the A294P mutant. Thus, under certain conditions, nonfunctional alleles act in a dominantnegative way on functional but relatively unstable mutated alleles. However, in heterozygous individuals carrying one wild-type allele, the disease is recessive, probably due to the stability of the wild-type enzyme.

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“…It also inhibits CRAD potently. Phenylarsine oxide, which forms covalent adducts between spatially-proximal sulfhydryl groups (45), inhibits CRAD, as it does RoDH-1 and RoDH-2. 4-Methylpyrazole, a potent inhibitor of the medium-chain alcohol dehydrogenase ADH class I and a moderate inhibitor of alcohol dehydrogenase class II, inhibits CRAD.…”

Section: Cis-retinol/androgen Short-chain Dehydrogenasementioning

confidence: 99%

cDNA Cloning and Characterization of a cis-Retinol/3α-Hydroxysterol Short-chain Dehydrogenase

Chai

Zhai

Napoli

1997

Journal of Biological Chemistry

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We report a mouse cDNA that encodes a 317-amino acid short-chain dehydrogenase which recognizes as substrates 9-cis-retinol, 11-cis-retinol, 5␣-androstan-3␣,17␤-diol, and 5␣-androstan-3␣-ol-17-one. This cis-retinol/androgen dehydrogenase (CRAD) shares closest amino acid similarity with mouse retinol dehydrogenase isozymes types 1 and 2 (86 and 91%, respectively). Recombinant CRAD uses NAD ؉ as its preferred cofactor and exhibits cooperative kinetics for cis-retinoids, but Michaelis-Menten kinetics for 3␣-hydroxysterols. Unlike recombinant retinol dehydrogenase isozymes, recombinant CRAD was inhibited by 4-methylpyrazole, was not stimulated by ethanol, and did not require phosphatidylcholine for optimal activity. CRAD mRNA was expressed intensely in kidney and liver, in contrast to retinol dehydrogenase isozymes, which show strong mRNA expression only in liver. CRAD mRNA expression was widespread (relative abundance): kidney (100) > liver (92) > small intestine (9) ‫؍‬ heart (9) > retinal pigment epithelium and sclera (4.5) > brain (2) > retina and vitreous (1.6) > spleen (0.7) > testis (0.6) > lung (0.4). CRAD may catalyze the first step in an enzymatic pathway from 9-cis-retinol to generate the retinoid X receptor ligand 9-cis-retinoic acid and/or may regenerate dihydrotestosterone from its catabolite 5␣-androstan-3␣,17␤-diol. These data also illustrate the multifunctional nature of short-chain dehydrogenases and provide a potential mechanism for androgen-retinoid interactions.The retinol (vitamin A) metabolite all-trans-retinoic acid modulates the transcription of multiple genes in diverse cells during embryogenesis and post-natally by activating three retinoic acid receptors, RAR␣, 1 RAR␤, and RAR␥ (1-3). An isomer of all-trans-retinoic acid, 9-cis-retinoic acid also binds with these three receptors with K d values in vitro similar to those of all-trans-retinoic acid. 9-cis-Retinoic acid, but not all-transretinoic acid, activates three other members of the steroid hormone/thyroid hormone/vitamin D/retinoid receptor superfamily, the RXRs ␣, ␤, and ␥ (4 -6). RARs and RXRs function as heterodimers. RXRs also serve as partners for other members of the superfamily, such as thyroid hormone, vitamin D, and peroxisome proliferator-activated receptors, and can modulate gene expression as homodimers (2, 3). This multiplicity of receptors, receptor partners, and ligands suggests a mechanism for the pleiotropic effects of retinoids, but much depends on the loci of all-trans-retinoic acid and 9-cis-retinoic acid biosynthesis. Even though 9-cis-retinoic acid occurs in vivo, and has been identified as an endogenous ligand of RXR, its concentrations are lower than all-trans-retinoic acid, and it has been found only in a few tissues to date, compared with the ubiquitous distribution of all-trans-retinoic acid (7,8). Rapid conversion in vivo into the receptor inactive isomer 9,13-di-cis-RA most likely limits 9-cis-retinoic acid concentrations and effects (9, 10).All-trans-retinoic acid undergoes isomerization in cultured cells...

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Primary Structure of Human 11-cisRetinol Dehydrogenase and Organization and Chromosomal Localization of the Corresponding Gene

Cited by 62 publications

References 0 publications

Inhibition of the visual cycle in vivo by 13 -cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Inhibition of the visual cycle in vivo by 13 -cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Biochemical Defects in 11-cis-Retinol Dehydrogenase Mutants Associated with Fundus Albipunctatus

cDNA Cloning and Characterization of a cis-Retinol/3α-Hydroxysterol Short-chain Dehydrogenase

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