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Molecular and Cellular Biology, June 2000, p. 4275-4287, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Disruption of the 11-cis-Retinol
Dehydrogenase Gene Leads to Accumulation of cis-Retinols and
cis-Retinyl Esters
Carola A. G. G.
Driessen,1,*
Huub J.
Winkens,1
Kirstin
Hoffmann,2
Leonoor D.
Kuhlmann,1
Bert P. M.
Janssen,1
Anke H. M.
Van
Vugt,1
J. Preston
Van
Hooser,3
B. E.
Wieringa,4
August F.
Deutman,1
Krzysztof
Palczewski,3,5,6
Klaus
Ruether,2 and
Jacques
J. M.
Janssen1
Department of Ophthalmology, University of Nijmegen, 6525 EX Nijmegen, The Netherlands1;
Department of Ophthalmology, Humboldt University, 15553 Berlin,
Germany2; Departments of
Ophthalmology,3
Chemistry,5 and
Pharmacology,6 University of
Washington, Seattle, Washington 98195; and Department of Cell
Biology, University of Nijmegen, 6500 HB Nijmegen, The
Netherlands4
Received 28 January 2000/Accepted 13 March 2000
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.
*
Corresponding author. Mailing address: Department of
Ophthalmology, University of Nijmegen, Philips van Leijdenlaan
15, 6525 EX Nijmegen, The Netherlands. Phone: 31243615160. Fax: 31243540522. E-mail:
c.driessen{at}ohk.azn.nl.
Molecular and Cellular Biology, June 2000, p. 4275-4287, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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