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PMID: 10825191 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters.

Molecular and cellular biology ·Vol. 20 ·No. 12 ·2000-06-00 ·Pages 4275-87

Driessen CA, Winkens HJ, Hoffmann K, Kuhlmann LD, Janssen BP, Van Vugt AH, Van Hooser JP, Wieringa BE, Deutman AF, Palczewski K, Ruether K, Janssen JJ

Abstract

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.

MeSH Terms
Alcohol Oxidoreductases/genetics,metabolism Animals Gene Deletion Gene Expression Regulation, Enzymologic Humans Mice Mice, Knockout Retinoids/metabolism Vision, Ocular
Chemicals
Retinoids Alcohol Oxidoreductases retinol dehydrogenase
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Driessen C A
Department of Ophthalmology, University of Nijmegen, The Netherlands. c.driessen@ohk.azn.nl
Winkens H J
Hoffmann K
Kuhlmann L D
Janssen B P
Van Vugt A H
Van Hooser J P
Wieringa B E
Deutman A F
Palczewski K
Ruether K
Janssen J J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.12.4275-4287.2000
Email
c.driessen@ohk.azn.nl
Published
2000-06-00
Pages
4275-87
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85795
Subset
IM
Grants
NEI NIH HHS · R01 EY009339 · United States
NEI NIH HHS · EY09339 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.12.4275-4287.2000 PMC Full Text View journal details
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