RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12.

@article{Molday2013RD3GD,
  title={RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12.},
  author={Laurie L Molday and Hidayat R. Djajadi and Paul Yan and Lukasz Szczygiel and Sanford L. Boye and Vince A. Chiodo and Kevin Gregory-Evans and Marinko Sarunic and William W. Hauswirth and Robert S. Molday},
  journal={Human molecular genetics},
  year={2013},
  volume={22 19},
  pages={
          3894-905
        }
}
RD3 is a 23 kDa protein implicated in the stable expression of guanylate cyclase in photoreceptor cells. Truncation mutations are responsible for photoreceptor degeneration and severe early-onset vision loss in Leber congenital amaurosis 12 (LCA12) patients, the rd3 mouse and the rcd2 collie. To further investigate the role of RD3 in photoreceptors and explore gene therapy as a potential treatment for LCA12, we delivered adeno-associated viral vector (AAV8) with a Y733F capsid mutation and… 

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Insights into the role of RD3 in guanylate cyclase trafficking, photoreceptor degeneration, and Leber congenital amaurosis
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Adeno-associated viral vector delivery of the normal RD3 gene to photoreceptors of the rd3 mouse restores GC1 and GC2 expression and outer segment localization and leads to the long-term recovery of visual function and photoreceptor cell survival.
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It is shown that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation, and the involvement ofGCAPs-induced ER stress in the physiopathology of Leber’s congenital amaurosis 12 (LCA12), will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.
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Evidence that RD3 protects photoreceptors from degeneration by competing with guanylyl cyclase-activating proteins (GCAPs) is presented, which supports the hypothesis that an essential biological function of RD3 is competition with GCAPs that inhibits premature cyclase activation in the inner segment.
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It is shown by immunohistochemistry of mouse retina sections that RD3 and guanylate kinase co-localize in photoreceptor inner segments and to a lesser extent in the outer plexiform layer, pointing toward a more complex function of RD3 inPhotoreceptors.
Functional study of two biochemically unusual mutations in GUCY2D Leber congenital amaurosis expressed via adenoassociated virus vector in mouse retinas
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Functional Study and Mapping Sites for Interaction with the Target Enzyme in Retinal Degeneration 3 (RD3) Protein *
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It is concluded that the main RetGC-binding interface on RD3 required for the negative regulation of the cyclase localizes to the Lys87–Leu122 region.
The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice*
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This mouse model provides the first direct biochemical and physiological in vivo evidence for the Arg838 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.
Retinal degeneration 3 (RD3) protein, a retinal guanylyl cyclase regulator, forms a monomeric and elongated four-helix bundle
TLDR
The NMR structure of RD3 presented here provides a structural basis for elucidating RD3–RetGC interactions relevant for normal vision or blindness.
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