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Nduka Enemchukwu, HUI XU, Mackenzie Parker, Lynn Zhu, Yingbin Fu; Long term protection of cone photoreceptors in a mouse model of Leber congenital amaurosis-1 by deletion of S-opsin. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4530.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in GUCY2D, the gene encoding guanylate cyclase 1 (GC1), cause Leber congenital amaurosis-1 (LCA1), the most severe form of early-onset inherited blinding disease. Previous studies have shown that both medium (M)- and short-wavelength (S)-opsins are mislocalized in GC1 knockout Gucy2e-/- mice. In addition, ventral and central cones degenerate more rapidly than dorsal cones in Gucy2e-/- mice. The objectives were to investigate why ventral and central cones degenerate much more rapidly than dorsal cones in this murine LCA1 model.
We used the Gucy2e-/- mouse model to examine our hypothesis that mouse S-opsin is more likely to cause cone degeneration than mouse M-opsin in LCA1 mouse model. Subcellular localization of mouse M and S opsins was examined by immunohistochemistry. The mRNA and protein levels of cone opsins were analyzed by real-time RT-PCR and western blotting, respectively, at two stages of cone degeneration, 1) 2-week, pre-degeneration, and 2) 5-week, early-stage degeneration. The role of S-opsin in Gucy2e-/- cone degeneration was determined by genetic deletion of S-opsin and assessment of cone survival.
Although both M and S cone opsins mistrafficked, as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Gucy2e-/- cones before the onset of massive ventral/central cone degeneration. Whereas approximately 90% of the cones in the central and ventral regions of Gucy2e–/– retina, respectively, degenerated within ten weeks, deletion of a single allele of S-opsin (Gucy2e–/–Opn1sw+/–) maintained 50% of the cones in the central and ventral regions for at least 10 weeks. By six months, all central and ventral region cones in Gucy2e–/– were degenerated. However, deletion of both alleles of S-opsin (Gucy2e–/–Opn1sw–/–) maintained 100% of the cones in the central and ventral regions for at least nine months. These findings suggest a dose dependent and progressive pathological effect of S-opsin in Gucy2e–/– retinas.
Our results suggest that S-opsin accumulation is responsible for the rapid cone degeneration in the central and ventral retina of Gucy2e–/– mice.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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