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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-17880

Samardzija, M; Tanimoto, N; Kostic, C; Beck, S; Oberhauser, V; Joly, S; Thiersch, M; Fahl, E; Arsenijevic, Y; von Lintig, J; Wenzel, A; Seeliger, M W; Grimm, C (2009). In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death. Human Molecular Genetics, 18(7):1266-1275.

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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.


31 citations in Web of Science®
26 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
Dewey Decimal Classification:610 Medicine & health
Deposited On:20 Mar 2009 13:28
Last Modified:05 Apr 2016 13:11
Publisher:Oxford University Press
Funders:Swiss National Science Foundation (grant numbers 3100A0-105793 and 3100A0-117760), University of Zurich Forschungskredit, ProVisu Foundation
Publisher DOI:10.1093/hmg/ddp026
PubMed ID:19147682

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