Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis

Hum Mol Genet. 2015 Mar 15;24(6):1755-63. doi: 10.1093/hmg/ddu588. Epub 2014 Nov 20.


Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA), a severe hereditary blindness occurring in early childhood. The pathology is attributed to a combination of 11-cis-retinal deficiency and photoreceptor degeneration. The mistrafficking of cone membrane-associated proteins including cone opsins (M- and S-opsins), cone transducin (Gαt2), G-protein-coupled receptor kinase 1 (GRK1) and guanylate cyclase 1 (GC1) has been suggested to play a role in cone degeneration. However, their precise role in cone degeneration is unclear. Here we investigated the role of S-opsin (Opn1sw) in cone degeneration in Lrat(-) (/-), a murine model for LCA, by genetic ablation of S-opsin. We show that deletion of just one allele of S-opsin from Lrat(-) (/-) mice is sufficient to prevent the rapid cone degeneration for at least 1 month. Deletion of both alleles of S-opsin prevents cone degeneration for an extended period (at least 12 months). This genetic prevention is accompanied by a reduction of endoplasmic reticulum (ER) stress in Lrat(-) (/-) photoreceptors. Despite cone survival in Opn1sw(-/-)Lrat(-) (/-) mice, cone membrane-associated proteins (e.g. Gαt2, GRK1 and GC1) continue to have trafficking problems. Our results suggest that cone opsins are the 'culprit' linking 11-cis-retinal deficiency to cone degeneration in LCA. This result has important implications for the current gene therapy strategy that emphasizes the need for a combinatorial therapy to both improve vision and slow photoreceptor degeneration.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / genetics
  • Gene Deletion*
  • Leber Congenital Amaurosis / genetics
  • Leber Congenital Amaurosis / pathology*
  • Mice
  • Protein Transport
  • Retinal Cone Photoreceptor Cells / ultrastructure*
  • Retinal Degeneration / genetics
  • Retinal Degeneration / pathology*
  • Retinal Degeneration / prevention & control
  • Rod Opsins / genetics*


  • Rod Opsins
  • short-wavelength opsin