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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 (Gα t2 ), 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.

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