In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death.

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Serval ID
serval:BIB_FFCE10CC2F55
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death.
Journal
Human molecular genetics
Author(s)
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.
ISSN
1460-2083[electronic]
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
18
Number
7
Pages
1266-75
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Abstract
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.
Keywords
Amino Acid Substitution, Animals, Carrier Proteins/genetics, Cell Death, Cone Opsins/metabolism, Eye Proteins/genetics, Humans, Mice, Mutation/genetics, Protein Transport, Retinal Cone Photoreceptor Cells/cytology, Retinal Cone Photoreceptor Cells/metabolism, Retinal Pigments/metabolism, Retinal Rod Photoreceptor Cells/metabolism, Retinaldehyde/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
29/09/2009 15:55
Last modification date
25/09/2019 7:11
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