Human Molecular Genetics Advance Access originally published online on January 15, 2009
Human Molecular Genetics 2009 18(7):1266-1275; doi:10.1093/hmg/ddp026
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In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death
1 Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Frauenklinikstr. 24, CH-8091 Zurich, Switzerland 2 Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Schleichstrasse 4/3, D-72076 Tuebingen, Germany 3 Unit of Gene Therapy and Stem Cell Biology, Jules Gonin Eye Hospital, University of Lausanne, 15 Avenue de France, CH-1004 Lausanne, Switzerland 4 Institute of Biology I, Animal Physiology and Neurobiology, University of Freiburg, Hauptstr. 1, D-79104 Freiburg, Germany
* To whom correspondence should be addressed. Tel: +41 442553872; Fax: +41 442554385; Email: marijana.samardzija{at}usz.uzh.ch
Received December 9, 2008; Accepted January 13, 2009
RPE65 is a retinoid isomerase required for the production of 11-cis-retinal, the chromophore of both cone and rod visual pigments. We recently established an R91W knock-in mouse strain as homologous animal model for patients afflicted by this mutation in RPE65. These mice have impaired vision and can only synthesize minute amounts of 11-cis-retinal. Here, we investigated the consequences of this chromophore insufficiency on cone function and pathophysiology. We found that the R91W mutation caused cone opsin mislocalization and progressive geographic cone atrophy. Remnant visual function was mostly mediated by rods. Ablation of rod opsin corrected the localization of cone opsin and improved cone retinal function. Thus, our analyses indicate that under conditions of limited chromophore supply rods and cones compete for 11-cis-retinal that derives from regeneration pathway(s) which are reliant on RPE65. Due to their higher number and the instability of cone opsin, rods are privileged under this condition while cones suffer chromophore deficiency and degenerate. These findings reinforce the notion that in patients any effective gene therapy with RPE65 needs to target the cone-rich macula directly to locally restore the cones’ chromophore supply outside the reach of rods.
These authors contributed equally to this work.
Present address: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4965, USA.
¶ Present address: Novartis Pharma Schweiz AG, Monbijoustrasse 118, CH-3007 Bern, Switzerland.
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