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

Tao Zhang, Nduka O. Enemchukwu, Alex Jones, Shixian Wang, Emily Dennis, Carl B. Watt, Edward N Pugh Jr, Yingbin Fu

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8 Scopus citations

Abstract

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 (Gα<inf>t2</inf>), 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<sup>-/-</sup>, a murine model for LCA, by genetic ablation of S-opsin. We show that deletion of just one allele of S-opsin from Lrat<sup>-/-</sup> 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<sup>-/-</sup> photoreceptors. Despite cone survival in Opn1sw<sup>-/-</sup>Lrat<sup>-/-</sup> 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.

Original languageEnglish (US)
Article numberddu588
Pages (from-to)1755-1763
Number of pages9
JournalHuman Molecular Genetics
Volume24
Issue number6
DOIs
StatePublished - 2015

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Zhang, T., Enemchukwu, N. O., Jones, A., Wang, S., Dennis, E., Watt, C. B., Pugh Jr, E. N., & Fu, Y. (2015). Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis. Human Molecular Genetics, 24(6), 1755-1763. [ddu588]. https://doi.org/10.1093/hmg/ddu588