{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRetinal degeneration‐3 (RD3) is an evolutionarily conserved protein that is predominantly expressed in the retina and plays a critical role during early photoreceptor development. Initial studies in the rd3 mouse model identified a point mutation that introduces a premature stop codon, leading to a truncated protein and rapid degradation. This loss‐of-function mutation is correlated with early-onset retinal degeneration and severe visual impairment in both mice and human patients with Leber congenital amaurosis (LCA)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther investigations have revealed that RD3 is essential for the proper trafficking and expression of retinal guanylate cyclases (GC1 and GC2) in photoreceptor cells. RD3 binds directly to these cyclases and to guanylate cyclase-activating proteins (GCAPs), facilitating the export of guanylate cyclases from the endoplasmic reticulum to the outer segments. This process is critical for the synthesis of cGMP and the regulation of intracellular Ca²⁺ necessary for normal phototransduction. Disruption of RD3 function impairs these interactions, resulting in mislocalization of the cyclases and subsequent photoreceptor degeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional in vivo studies have provided further insights into the protective mechanism of RD3 in photoreceptor cells. RD3 not only prevents aberrant activation of retinal guanylate cyclases by GCAPs but also appears to regulate the formation of key protein complexes in the endoplasmic reticulum required for proper membrane targeting. Overexpression of RD3 via gene therapy has been shown to partially rescue photoreceptor function and slow degeneration in models of retinal dystrophy. These findings underscore the therapeutic potential of strategies aimed at restoring or enhancing RD3 function to combat recessive and even certain dominant forms of congenital blindness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "James S Friedman, Bo Chang, Chitra Kannabiran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/510021"}], "href": "https://doi.org/10.1086/510021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17186464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17186464"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Christiana L Cheng, Robert S Molday "}, {"type": "b", "children": [{"type": "t", "text": "Changes in gene expression associated with retinal degeneration in the rd3 mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2013)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23687432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23687432"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Seifollah Azadi, Laurie L Molday, Robert S Molday "}, {"type": "b", "children": [{"type": "t", "text": "RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1010460107"}], "href": "https://doi.org/10.1073/pnas.1010460107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21078983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21078983"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Laurie L Molday, Hidayat Djajadi, Paul Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt244"}], "href": "https://doi.org/10.1093/hmg/ddt244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23740938"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23740938"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rahel Zulliger, Muna I Naash, Raju V S Rajala, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.616656"}], "href": "https://doi.org/10.1074/jbc.M114.616656"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25477517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25477517"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Igor V Peshenko, Elena V Olshevskaya, Alexander M Dizhoor "}, {"type": "b", "children": [{"type": "t", "text": "Functional Study and Mapping Sites for Interaction with the Target Enzyme in Retinal Degeneration 3 (RD3) Protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.742288"}], "href": "https://doi.org/10.1074/jbc.M116.742288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27471269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27471269"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alexander M Dizhoor, Elena V Olshevskaya, Igor V Peshenko "}, {"type": "b", "children": [{"type": "t", "text": "Retinal degeneration-3 protein promotes photoreceptor survival by suppressing activation of guanylyl cyclase rather than accelerating GMP recycling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2021.100362"}], "href": "https://doi.org/10.1016/j.jbc.2021.100362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33539922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33539922"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Igor V Peshenko, Elena V Olshevskaya, Alexander M Dizhoor "}, {"type": "b", "children": [{"type": "t", "text": "Retinal degeneration-3 protein attenuates photoreceptor degeneration in transgenic mice expressing dominant mutation of human retinal guanylyl cyclase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2021.101201"}], "href": "https://doi.org/10.1016/j.jbc.2021.101201"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34537244"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34537244"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Bo Chang "}, {"type": "b", "children": [{"type": "t", "text": "Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber's Congenital Amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Methods Mol Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-1-4939-3661-8_21"}], "href": "https://doi.org/10.1007/978-1-4939-3661-8_21"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27150101"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27150101"}]}]}]}