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Human Molecular Genetics Advance Access published online on November 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi411
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 7, 2005
Revised October 28, 2005
Accepted October 28, 2005

Article

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

Debra A. Thompson 1*, Andreas R. Janecke 2, Jessica Lange 3, Kecia L. Feathers 4, Christian A. Hübner 3, Christina L. McHenry 4, David W. Stockton 5, Gabriele Rammesmayer 2, James R. Lupski 5, Guillermo Antinolo 6, Carmen Ayuso 7, Montserrat Baiget 8, Peter Gouras 9, John R. Heckenlively 4, Anneke den Hollander 10, Samuel G. Jacobson 11, Richard A. Lewis 5, Paul A. Sieving 12, Bernd Wissinger 13, Suzanne Yzer 14, Eberhart Zrenner 13, Gerd Utermann 2, and Andreas Gal 3

1 Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor MI 48105 USA; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor MI 48105 USA; W.K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor MI 48105
2 Department für Medizinische Genetik, Molekulare und Klinische Pharmakologie, Medizinische Universität Innsbruck, Innsbruck, Austria
3 Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
4 Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor MI 48105 USA
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030 USA
6 Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Seville, Spain
7 La Fundación Jiménez Díaz, Madrid, Spain
8 Hospital San Pau, Barcelona, Spain
9 Department of Ophthalmology, Columbia University, New York NY 10032, USA
10 Department Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
11 Scheie Eye Institute, University of Pennsylvania, Philadelphia PA 19104, USA
12 National Eye Institute, National Institutes of Health, Bethesda MD 20892, USA
13 Klinik für Augenheilkunde, Universität Tübingen, Tübingen, Germany
14 Department Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; The Rotterdam Eye Hospital, Rotterdam, The Netherlands; McGill Ocular Genetics Laboratory, McGill University Health Center, Montreal, Canada

* To whom correspondence should be addressed.
Debra A. Thompson, E-mail: dathom{at}umich.edu


  Abstract

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 retinal 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 signficantly reduced. For the p.M49T 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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