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PMID: 18296659 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Rpe65-/- and Lrat-/- mice: comparable models of leber congenital amaurosis.

Investigative ophthalmology & visual science ·Vol. 49 ·No. 6 ·2008-06-00 ·Pages 2384-9

Fan J, Rohrer B, Frederick JM, Baehr W, Crouch RK

Abstract

The Rpe65-/- mouse, used as a model for Leber congenital amaurosis, has slow rod degeneration and rapid cone loss, presumably because of the mistrafficking of cone opsins. This animal does not generate 11-cis retinal, and both cone loss and rod response are restored by 11-cis retinal administration. Similarly, the Lrat-/- mouse does not produce 11-cis retinal. The authors sought to determine whether the same effects on rod and cone opsins in the Rpe65-/- mouse are also present in the Lrat-/- mouse, thereby establishing that these changes can be attributed to the lack of 11-cis retinal rather than to some unknown function of RPE65. Rod and cone opsins were localized by immunohistochemical methods. Functional opsin levels were determined by regeneration with 11-cis retinal. Isorhodopsin levels were determined from pigment extraction. Opsin phosphorylation was determined by mass spectrometry. Rods in both models degenerated slowly. Regenerable rod opsin levels were similar over the 6-month time course investigated, rod opsin was phosphorylated at a low level (approximately 10%), and minimal 9-cis retinal was generated by a nonphotic process, giving a trace light response. In both models, S-opsin and M/L-opsin failed to traffic to the cone outer segments appropriately, and rapid cone degeneration occurred. Cone opsin mistrafficking in both models was arrested on 11-cis retinal administration. These data show that the Lrat-/- and Rpe65-/- mice are comparable models for studies of Leber congenital amaurosis and that the destructive cone opsin mistrafficking is caused by the lack of 11-cis retinal.

MeSH Terms
Acyltransferases/physiology Animals Blindness/congenital,metabolism,pathology Carrier Proteins/physiology Disease Models, Animal Eye Proteins/physiology Fluorescent Antibody Technique, Indirect Mice Mice, Knockout Phosphorylation Photoreceptor Cells, Vertebrate/metabolism Retinal Degeneration/congenital,metabolism,pathology Retinaldehyde/administration & dosage,deficiency Rod Opsins/metabolism cis-trans-Isomerases
Chemicals
Carrier Proteins Eye Proteins Rod Opsins Acyltransferases lecithin-retinol acyltransferase retinoid isomerohydrolase cis-trans-Isomerases Retinaldehyde
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fan Jie
Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina 29402, USA.
Rohrer Baerbel
Frederick Jeanne M
Baehr Wolfgang
Crouch Rosalie K
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Article Info
Journal
Investigative ophthalmology & visual science
Abbr.
Invest Ophthalmol Vis Sci
ISSN
0146-0404
DOI
10.1167/iovs.08-1727
Published
2008-06-00
Epub
2008-00-22
Pages
2384-9
Language
English
Region
United States
NLM ID
7703701
PMCID
PMC2641010
Subset
IM
Grants
NEI NIH HHS · EY13520 · United States
NEI NIH HHS · EY08123 · United States
NEI NIH HHS · R24 EY014793 · United States
NEI NIH HHS · EY14793 · United States
NEI NIH HHS · R01 EY004939-25 · United States
NCRR NIH HHS · C06 RR015455 · United States
NEI NIH HHS · R01 EY004939-24 · United States
NEI NIH HHS · R01 EY013520 · United States
NEI NIH HHS · R01 EY004939 · United States
NEI NIH HHS · EY014800-039003 · United States
NEI NIH HHS · EY04939 · United States
NEI NIH HHS · R01 EY008123 · United States
External Links
PubMed source DOI: 10.1167/iovs.08-1727 PMC Full Text View journal details
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