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J. Biol. Chem., Vol. 281, Issue 49, 37697-37704, December 8, 2006

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Retinol Dehydrogenase (RDH12) Protects Photoreceptors from Light-induced Degeneration in Mice^*

Akiko Maeda, Tadao Maeda, Yoshikazu Imanishi, Wenyu Sun, Beata Jastrzebska, Denise A. Hatala, Huub J. Winkens^¶, Klaus Peter Hofmann^||, Jacques J. Janssen^¶, Wolfgang Baehr^**, Carola A. Driessen, and Krzysztof Palczewski¹

From the Departments of Pharmacology and Ophthalmology, Case Western Reserve University, Cleveland, Ohio 44106, Departments of ^¶Ophthalmology and Biochemistry, University of Nijmegen, 6525 EX Nijmegen, The Netherlands, ^||Institut für Medizinische Physik und Biophysik, Universitätsklinikum Charité, Humboldt Universität zu Berlin, 10098 Berlin, Germany, and Departments of ^**Ophthalmology and Visual Sciences, Biology, and Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84112

RDH12 has been suggested to be one of the retinol dehydrogenases (RDH) involved in the vitamin A recycling system (visual cycle) in the eye. Loss of function mutations in the RDH12 gene were recently reported to be associated with autosomal recessive childhood-onset severe retinal dystrophy. Here we show that RDH12 localizes to the photoreceptor inner segments and that deletion of this gene in mice slows the kinetics of all-trans-retinal reduction, delaying dark adaptation. However, accelerated 11-cis-retinal production and increased susceptibility to light-induced photoreceptor apoptosis were also observed in Rdh12^-/- mice, suggesting that RDH12 plays a unique, nonredundant role in the photoreceptor inner segments to regulate the flow of retinoids in the eye. Thus, severe visual impairments of individuals with null mutations in RDH12 may likely be caused by light damage¹.

Received for publication, August 31, 2006 , and in revised form, October 2, 2006.

^* This research was supported by National Institutes of Health Grants EY09339 and P30 EY11373, a grant from the National Neurovision Research Institute (to A. M.), a center grant from the Foundation Fighting Blindness to the University of Utah, and by Landelijke stichting Blinden en Slechtzienden, Gelderse Blinden Stichting, Stichting OOG, Stichting Blindenhulp Rotterdamse Vereniging Blindenbelangen, and Stichting Ooglijders/Stichting het Hooykaas La Lau Fonds. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, Case Western Reserve University, BRB Bldg., 10900 Euclid Ave, Cleveland, OH 44106-4965. Tel.: 216-368-4631; Fax: 216-368-1300; E-mail: kxp65{at}case.edu

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