Disruption of the 11-cis-Retinol Dehydrogenase Gene Leads to Accumulation of cis-Retinols andcis-Retinyl Esters

Driessen, C.A.G.G.; Winkens, H.J.; Hoffmann, Kirstin; Kuhlmann, Leonoor D; Janssen, B. P. M.; Vugt, A.H.M. van; Hooser, J. Preston Van; Wieringa, Bé; Deutman, August F.; Palczewski, Krzysztof; Rüether, Klaus; Janssen, J.J.M.

doi:10.1128/mcb.20.12.4275-4287.2000

Cited by 115 publications

(103 citation statements)

References 43 publications

(56 reference statements)

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“…However, disabling mutations in men and mice produce no embryonic developmental abnormalities (16)(17)(18)(19). In this report, we provide unequivocal evidence that RDH11-14 display high activity toward 9-cis-and all-trans-retinol.…”

Section: Involvement Of Rdh11-14 In Retinoid Transformation and All-tsupporting

confidence: 53%

“…An enzyme encoded by the RDH5 gene (10,11), 11-cis-RDH, was proposed to be responsible for both 11-cis-retinal and 9-cis-retinal production due to its relaxed substrate specificity (12)(13)(14)(15). However, the disruption of this gene in a mouse model led to uninterrupted production of 11-cis-retinal (16,17) and a lack of any embryonic abnormalities. Furthermore, patients with fundus albipunctatus who also have a disabling mutation in the RDH5 gene still show efficient production of the chromophore, albeit with slower kinetics (18,19).…”

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confidence: 99%

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Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

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Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dualsubstrate specificity, uniquely metabolizing all-trans-and cis-retinols with C 15 pro-R specificity. RDH11-14 could be involved in the first step of all-trans-and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dualsubstrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cisretinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types, including those comprising the epithelium and immune system. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid receptors. All-trans-retinoic acid signals through specific interactions with the nuclear retinoic acid receptors, whereas its isomer, 9-cis-retinoic acid, is a high affinity ligand of retinoic acid receptors and retinoid X receptors. In the retina, light-dependent photoisomerization of 11-cis-retinylidene to the all-transretinylidene moiety of rod and cone photoreceptors is a key reaction that triggers visual * This research was supported by National Institutes of Health Grants EY08061, CA75173, and DK59125, a grant from Research to Prevent Blindness, Inc. (to the Department of Ophthalmology, University of Washington), and by the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Tables 1-3. § These authors contributed equally to this work. § § Recipient of a Research to Prevent Blindness Senior Investigator Award. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Seattle,; E-mail: palczews@u.washington.edu. Transformations of retinoids occur mostly through enzymatic or photochemical reactions, although they readily isomerize non-enzymatically to thermodynamic equilibriu...

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Section: Involvement Of Rdh11-14 In Retinoid Transformation and All-tsupporting

confidence: 53%

mentioning

confidence: 99%

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

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181

227

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“…C. Driessen and J. J. Janssen (15). Genotypes of Rdh5−/− mice were determined by PCR (15). Opsin−/− mice were obtained from Dr. J. Lem (Tufts University, Boston, MA).…”

Section: Experimental Procedures Animalsmentioning

confidence: 99%

“…Rdh5-deficient mice were previously generated and characterized by Drs. C. Driessen and J. J. Janssen (15). Genotypes of Rdh5−/− mice were determined by PCR (15).…”

Section: Experimental Procedures Animalsmentioning

confidence: 99%

“…Deletion of specific genes of the retinoid cycle, however, leads to severe abnormalities in ester levels. For example, the levels of all-trans-retinyl esters are highly elevated in Rpe65−/− mice (22), while in Rdh5−/− mice, 13-cis-retinyl ester levels are surprisingly high (15). RPE65 has been proposed to be the isomerase responsible for transformation of all-trans-retinyl esters to 11-cis-retinol (23)(24)(25)(26) (Figure 1).…”

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Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

Maeda

Imanishi

et al. 2006

Biochemistry

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Regeneration of the visual chromophore, 11-cis-retinal, is a critical step in restoring photoreceptors to their dark-adapted conditions. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and the retinal pigment epithelium (RPE). Disabling mutations in nearly all of the retinoid cycle genes are linked to human conditions that cause congenital or progressive defects in vision. Several mouse models with disrupted genes related to this cycle contain abnormal fatty acid retinyl ester levels in the RPE. To investigate the mechanisms of retinyl ester accumulation, we generated single or double knockout mice lacking retinoid cycle genes. Alltrans-retinyl esters accumulated in mice lacking RPE65, but they are reduced in double knockout mice also lacking opsin, suggesting a connection between visual pigment regeneration and the retinoid cycle. Only Rdh5-deficient mice accumulate cis-retinyl esters, regardless of the simultaneous disruption of RPE65, opsin, and prRDH. 13-cis-Retinoids are produced at higher levels when the flow of retinoid through the cycle was increased, and these esters are stored in specific structures called retinosomes. Most importantly, retinylamine, a specific and effective inhibitor of the 11-cisretinol formation, also inhibits the production of 13-cis-retinyl esters. The data presented here support the idea that 13-cis-retinyl esters are formed through an aberrant enzymatic isomerization process.Vitamin A transformations in the eye are essential for vision. Absorption of light by the vitamin A-derived chromophore of visual pigments, 11-cis-retinal, leads to its photoisomerization to all-trans-retinal and the initiation of the signal transduction cascade (1-4). Through a chain of reactions, all-trans-retinal is recycled enzymatically back to 11-cis-retinal (5-8). These retinoid cycle reactions (Figure 1) take place in the outer segments of photoreceptor cells and in the adjacent retinal pigment epithelium (RPE). 1 Characterization of the knockout mice lacking genes involved in the retinoid cycle provides important insight into the flow of retinoids in the eye.11-cis-Retinol dehydrogenase (RDH), also known as RDH5, catalyzes the final oxidation reaction of 11-cis-retinol in the RPE (9, 10). Although RDH5 is responsible for the majority of 11-cis-RDH activity, RDH11 and other RDHs also have a measurable role in regenerating the visual pigment by complementing RDH5 in RPE cells (11). Disruption of the gene encoding RDH5 causes fundus albipunctatus in humans (12,13). Fundus albipunctatus is an autosomal recessive form of congenital stationary night blindness characterized by the appearance of numerous small white dots located in the RPE, a delayed course of dark adaptation, and † This research was supported by NIH Grant EY09339. Lipid droplet-like organelles known as retinosomes were characterized as specific sites of alltrans-retinyl ester accumulation in the RPE (19,20). All-trans-retinyl esters accumulate in the RPE of wild-type mice as the...

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Fluorescence Adaptive Optics Scanning Laser Ophthalmoscope for Detection of Reduced Cones and Hypoautofluorescent Spots in Fundus Albipunctatus

et al. 2014

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IMPORTANCE Fundus albipunctatus (FA) is a form of congenital stationary night blindness characterized by yellow-white spots, which were classically described as subretinal. Although night blindness and delayed dark adaptation are hallmarks of this condition, recent studies have described a macular phenotype, particularly among older patients. Using a fluorescence adaptive optics scanning laser ophthalmoscope (FAOSLO), this study provides in vivo morphologic data at the cellular level in FA.OBJECTIVE To study the cone photoreceptors and the albipunctate spots in FA at single-cell resolution. DESIGN, SETTING, AND PARTICIPANTA woman in her 30s with FA underwent a complete ophthalmic examination, including conventional imaging tests, at the University of Rochester. A FAOSLO was used to obtain infrared reflectance images of the cone mosaic at the central fovea and along the superior and temporal meridians to 10°eccentricity. Cone density was measured at the foveal center, and cone spacing was calculated in sampling windows eccentrically. In the area of the albipunctate spots, autofluorescence FAOSLO images (excitation, 561 nm; emission, 624 Δ 40 nm) were simultaneously obtained. MAIN OUTCOMES AND MEASURESStructural appearance of cones, cone density and spacing, and reflectance and autofluorescence of albipunctate spots.RESULTS Cone density was reduced to 70% of the lower limit of the normal range at the foveal center (78.7 × 10 3 cones/mm 2 ; mean [SD] reference range, 199 [87] × 10 3 cones/mm 2 ), and cone spacing was increased eccentrically to 10°(sign test, P = .045). Individual cone central core reflectances appeared dim, suggesting loss of photoreceptor outer segments. The albipunctate spots were hypoautofluorescent. No photoreceptors or retinal pigment epithelium cells were identified at the locations of the albipunctate spots. CONCLUSIONS AND RELEVANCEAlthough the predominant clinical symptom of night blindness and the electroretinography results suggest a primary rod dysfunction, examination with a FAOSLO demonstrates that cone density is also reduced. This finding may represent an early sign of progression to macular phenotype in FA. The hypoautofluorescence suggests that the albipunctate spots do not represent lipofuscin.

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Disruption of the 11-cis-Retinol Dehydrogenase Gene Leads to Accumulation of cis-Retinols andcis-Retinyl Esters

Cited by 115 publications

References 43 publications

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

Fluorescence Adaptive Optics Scanning Laser Ophthalmoscope for Detection of Reduced Cones and Hypoautofluorescent Spots in Fundus Albipunctatus

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