Human Molecular Genetics Advance Access originally published online on October 12, 2007
Human Molecular Genetics 2008 17(2):281-292; doi:10.1093/hmg/ddm304
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R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal
1 Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Frauenklinikstr. 24, 8091 Zurich, Switzerland 2 Institute of Biology I, Animal Physiology and Neurobiology, University of Freiburg, Hauptstr. 1, D-79104 Freiburg, Germany 3 Ocular Neurodegeneration Research Group, Institute for Ophthalmic Research, University of Tuebingen, Schleichstr. 4/3, D-72076 Tuebingen, Germany
* To whom correspondence should be addressed at Tel: +41 442553872; Fax: +41 442554385; E-mail: samam{at}opht.uzh.ch
Received September 18, 2007; Accepted October 10, 2007
RPE65 is a retinal pigment epithelial protein essential for the regeneration of 11-cis-retinal, the chromophore of cone and rod visual pigments. Mutations in RPE65 lead to a spectrum of retinal dystrophies ranging from Leber’s congenital amaurosis to autosomal recessive retinitis pigmentosa. One of the most frequent missense mutations is an amino acid substitution at position 91 (R91W). Affected patients have useful cone vision in the first decade of life, but progressively lose sight during adolescence. We generated R91W knock-in mice to understand the mechanism of retinal degeneration caused by this aberrant Rpe65 variant. We found that in contrast to Rpe65 null mice, low but substantial levels of both RPE65 and 11-cis-retinal were present. Whereas rod function was impaired already in young animals, cone function was less affected. Rhodopsin metabolism and photoreceptor morphology were disturbed, leading to a progressive loss of photoreceptor cells and retinal function. Thus, the consequences of the R91W mutation are clearly distinguishable from an Rpe65 null mutation as evidenced by the production of 11-cis-retinal and rhodopsin as well as by less severe morphological and functional disturbances at early age. Taken together, the pathology in R91W knock-in mice mimics many aspects of the corresponding human blinding disease. Therefore, this mouse mutant provides a valuable animal model to test therapeutic concepts for patients affected by RPE65 missense mutations.
Present address: Novartis Pharma Schweiz AG—BU Ophthalmics, Monbijoustrasse 118, CH-3007 Bern, Switzerland.
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