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Nduka O Enemchukwu, Tao Zhang, Alex Jones, Shixian Wang, Emily Dennis, Carl B Watt, Edward Pugh, Yingbin Fu; Genetic deletion of S-opsin provides long-term protection of cone photoreceptors in a mouse model of Leber congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5478.
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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 (Gat2), G-protein-coupled receptor kinase 1 (GRK1), and guanylate cyclase 1 (GC1) is 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 bred Lrat-/- mice with S-opsin-/- mice to generate Lrat-/-S-opsin-/- and Lrat-/-S-opsin+/- mice. We compared the cone density between Lrat-/-, Lrat-/-S-opsin+/-, Lrat-/-S-opsin-/-, and WT mouse lines at 1, 6, and 12 month by cone density analysis. Cone morphology of different mouse lines were analyzed by histology and electron microscopy. We also evaluated ER stress by visualizing C/EBP homology protein (CHOP).
Deletion of just one allele of S-opsin from Lrat-/- mice is sufficient to prevent the rapid cone degeneration in the ventral and central retina for at least one 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. Gat2, 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.
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