{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:47:51Z","timestamp":1792000071752,"version":"4.4.0"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP16010"],"award-info":[{"award-number":["GGP16010"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007052","name":"Universit\u00e0 degli Studi di Verona","doi-asserted-by":"publisher","award":["Joint project 2018, grant no. JPVR184ZZ5"],"award-info":[{"award-number":["Joint project 2018, grant no. JPVR184ZZ5"]}],"id":[{"id":"10.13039\/501100007052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005743","name":"Universit\u00e0 Cattolica del Sacro Cuore","doi-asserted-by":"publisher","award":["Core grants linea D1"],"award-info":[{"award-number":["Core grants linea D1"]}],"id":[{"id":"10.13039\/501100005743","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Retina Italia","award":["unrestricted grant"],"award-info":[{"award-number":["unrestricted grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Guanylate cyclase-activating protein 1 (GCAP1) is involved in the shutdown of the phototransduction cascade by regulating the enzymatic activity of retinal guanylate cyclase via a Ca2+\/cGMP negative feedback. While the phototransduction-associated role of GCAP1 in the photoreceptor outer segment is widely established, its implication in synaptic transmission to downstream neurons remains to be clarified. Here, we present clinical and biochemical data on a novel isolate GCAP1 variant leading to a double amino acid substitution (p.N104K and p.G105R) and associated with cone dystrophy (COD) with an unusual phenotype. Severe alterations of the electroretinogram were observed under both scotopic and photopic conditions, with a negative pattern and abnormally attenuated b-wave component. The biochemical and biophysical analysis of the heterologously expressed N104K-G105R variant corroborated by molecular dynamics simulations highlighted a severely compromised Ca2+-sensitivity, accompanied by minor structural and stability alterations. Such differences reflected on the dysregulation of both guanylate cyclase isoforms (RetGC1 and RetGC2), resulting in the constitutive activation of both enzymes at physiological levels of Ca2+. As observed with other GCAP1-associated COD, perturbation of the homeostasis of Ca2+ and cGMP may lead to the toxic accumulation of second messengers, ultimately triggering cell death. However, the abnormal electroretinogram recorded in this patient also suggested that the dysregulation of the GCAP1\u2013cyclase complex further propagates to the synaptic terminal, thereby altering the ON-pathway related to the b-wave generation. In conclusion, the pathological phenotype may rise from a combination of second messengers\u2019 accumulation and dysfunctional synaptic communication with bipolar cells, whose molecular mechanisms remain to be clarified.<\/jats:p>","DOI":"10.3390\/ijms22084030","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T15:30:39Z","timestamp":1618414239000},"page":"4030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Impaired Ca2+ Sensitivity of a Novel GCAP1 Variant Causes Cone Dystrophy and Leads to Abnormal Synaptic Transmission Between Photoreceptors and Bipolar Cells"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-3717","authenticated-orcid":false,"given":"Valerio","family":"Marino","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuditta","family":"Dal Cortivo","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-4937","authenticated-orcid":false,"given":"Paolo Enrico","family":"Maltese","sequence":"additional","affiliation":[{"name":"MAGI\u2019S Lab S.R.L., 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Placidi","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d, IRCCS, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"De Siena","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d, IRCCS, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1694-1062","authenticated-orcid":false,"given":"Benedetto","family":"Falsini","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d, IRCCS, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-221X","authenticated-orcid":false,"given":"Matteo","family":"Bertelli","sequence":"additional","affiliation":[{"name":"MAGI\u2019S Lab S.R.L., 38068 Rovereto, Italy"},{"name":"MAGI Euregio, 39100 Bolzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3724-3044","authenticated-orcid":false,"given":"Daniele","family":"Dell\u2019Orco","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, 37129 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1021\/cn400027z","article-title":"A calcium-relay mechanism in vertebrate phototransduction","volume":"4","author":"Koch","year":"2013","journal-title":"ACS Chem. 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