title: Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis.
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 (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.
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Nduka O
authors.initials: NO
authors.lastname: Enemchukwu
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Alex
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Shixian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Emily
authors.initials: E
authors.lastname: Dennis
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Carl B
authors.initials: CB
authors.lastname: Watt
authors.affiliation: Physiology and Membrane Biology, University of California, Davis, 3301 Tupper Hall, 1 Shields Avenue, Davis, CA 95616, USA.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Pugh
authors.affiliation: Department of Ophthalmology and Visual Sciences, Department of Neurobiology and Anatomy, University of Utah Health Sciences Center, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA yingbin.fu@hsc.utah.edu.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D017353:Gene Deletion; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000473:pathology*; D051379:Mice; D021381:Protein Transport; D017949:Retinal Cone Photoreceptor Cells / Q000648:ultrastructure*; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D017299:Rod Opsins / Q000235:genetics*
chemical_list: D017299:Rod Opsins; C095853:short-wavelength opsin