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

Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2384-9. doi: 10.1167/iovs.08-1727. Epub 2008 Feb 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / physiology*
  • Animals
  • Blindness / congenital
  • Blindness / metabolism*
  • Blindness / 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
  • Retinal Degeneration / metabolism*
  • Retinal Degeneration / pathology
  • Retinaldehyde / administration & dosage
  • Retinaldehyde / deficiency
  • Rod Opsins / metabolism
  • cis-trans-Isomerases


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