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Human Molecular Genetics Advance Access originally published online on November 3, 2005
Human Molecular Genetics 2005 14(24):3865-3875; doi:10.1093/hmg/ddi411
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Debra A. Thompson1,2,*, Andreas R. Janecke3, Jessica Lange4, Kecia L. Feathers1, Christian A. Hübner4, Christina L. McHenry1, David W. Stockton5, Gabriele Rammesmayer3, James R. Lupski5, Guillermo Antinolo6, Carmen Ayuso7, Montserrat Baiget8, Peter Gouras9, John R. Heckenlively1, Anneke den Hollander10, Samuel G. Jacobson11, Richard A. Lewis5, Paul A. Sieving12, Bernd Wissinger13, Suzanne Yzer10,14,15, Eberhart Zrenner13, Gerd Utermann3 and Andreas Gal4

1Department of Ophthalmology and Visual Sciences, 2Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48105, USA, 3Department für Medizinische Genetik, Molekulare und Klinische Pharmakologie, Medizinische Universität Innsbruck, Innsbruck, Austria, 4Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, 5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, 6Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Seville, Spain, 7La Fundación Jiménez Díaz, Madrid, Spain, 8Hospital San Pau, Barcelona, Spain, 9Department of Ophthalmology, Columbia University, New York, NY 10032, USA, 10Department Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 11Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA, 12National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA, 13Klinik für Augenheilkunde, Universität Tübingen, Tübingen, Germany, 14The Rotterdam Eye Hospital, Rotterdam, The Netherlands and 15McGill Ocular Genetics Laboratory, McGill University Health Center, Montreal, Canada

* To whom correspondence should be addressed at: W.K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA. Tel: +1 7349369504; Fax: +1 7346470228; Email: dathom{at}umich.edu

Received September 7, 2005; Accepted October 28, 2005

Retinoid dehydrogenases/reductases catalyze key oxidation–reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.


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