Rpe65-/- and Lrat-/- mice:: Comparable models of Leber congenital amaurosis

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.