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

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Jie Fan, Baerbel Rohrer, Jeanne M Frederick, Wolfgang Baehr, Rosalie K Crouch
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 49 Issue 6 Pg. 2384-9 (Jun 2008) ISSN: 0146-0404 [Print] United States
• PMID: 18296659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Eye Proteins
• Rod Opsins
• Acyltransferases
• lecithin-retinol acyltransferase
• retinoid isomerohydrolase
• cis-trans-Isomerases
• Retinaldehyde

Topics

• 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