Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis

Proc Natl Acad Sci U S A. 2011 May 24;108(21):8879-84. doi: 10.1073/pnas.1017127108. Epub 2011 May 9.


Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat(-)(/-), a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat(-)(/-) cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65(-)(/-) and Lrat(-)(/-) LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lrat(-)(/-) retina and transfected cells. Replacing rhodopsin with S-opsin in Lrat(-)(/-) rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA.

Publication types

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

MeSH terms

  • Acyltransferases / deficiency
  • Acyltransferases / genetics
  • Animals
  • Cone Opsins / physiology*
  • Endoplasmic Reticulum / pathology
  • Humans
  • Leber Congenital Amaurosis / pathology*
  • Mice
  • Mice, Knockout
  • Protein Transport
  • Retinal Cone Photoreceptor Cells / pathology*
  • Retinitis Pigmentosa / etiology
  • Rhodopsin
  • Time Factors


  • Cone Opsins
  • Rhodopsin
  • Acyltransferases
  • lecithin-retinol acyltransferase