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.
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Authors | Tao Zhang, Nduka O Enemchukwu, Alex Jones, Shixian Wang, Emily Dennis, Carl B Watt, Edward N Pugh Jr, Yingbin Fu |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 24
Issue 6
Pg. 1755-63
(Mar 15 2015)
ISSN: 1460-2083 [Electronic] England |
PMID | 25416279
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. |
Chemical References |
- Rod Opsins
- short-wavelength opsin
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Topics |
- Animals
- Disease Models, Animal
- Endoplasmic Reticulum Stress
(genetics)
- Gene Deletion
- Leber Congenital Amaurosis
(genetics, pathology)
- Mice
- Protein Transport
- Retinal Cone Photoreceptor Cells
(ultrastructure)
- Retinal Degeneration
(genetics, pathology, prevention & control)
- Rod Opsins
(genetics)
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