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The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca<jats:sup>2+<\/jats:sup>-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca<jats:sup>2+<\/jats:sup>-free form at photoreceptor inner segments. We here show that the retinal degeneration in <jats:italic>rd3<\/jats:italic> mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in <jats:italic>rd3<\/jats:italic> mice, it takes 8 months to halve in <jats:italic>rd3\/rd3<\/jats:italic> GCAPs<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in <jats:italic>rd3<\/jats:italic> mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca<jats:sup>2+<\/jats:sup>-free-phosphorylated state in <jats:italic>rd3<\/jats:italic> mice, we infer that the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca<jats:sup>2+<\/jats:sup>-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of <jats:italic>rd3<\/jats:italic> retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber\u2019s congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.<\/jats:p>","DOI":"10.1038\/s41419-020-2255-0","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T09:03:03Z","timestamp":1579856583000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress"],"prefix":"10.1038","volume":"11","author":[{"given":"Anna","family":"Plana-Bonamais\u00f3","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-8919","authenticated-orcid":false,"given":"Santiago","family":"L\u00f3pez-Begines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Andilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Fidalgo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Loza-Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8621-0057","authenticated-orcid":false,"given":"Josep Mar\u00eda","family":"Estanyol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro de la","family":"Villa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6393-1644","authenticated-orcid":false,"given":"Ana","family":"M\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,24]]},"reference":[{"key":"2255_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.neuron.2005.10.014","volume":"48","author":"ME Burns","year":"2005","unstructured":"Burns, M. 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