{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T03:40:07Z","timestamp":1793504407503,"version":"4.5.0"},"posted":{"date-parts":[[2025,12,17]]},"group-title":"Physiology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Department of Veterans Affairs, Office of Research and Development, Merit Review grant","award":["I01 BX002137"],"award-info":[{"award-number":["I01 BX002137"]}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["1R01HL164415"],"award-info":[{"award-number":["1R01HL164415"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Department of Defense award number","award":["W81XWH-21-1-0424"],"award-info":[{"award-number":["W81XWH-21-1-0424"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["AHA.25POST1361676"],"award-info":[{"award-number":["AHA.25POST1361676"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Inherited arrhythmia syndromes are caused by genetic variants that alter cardiac ion channel function. We investigated a complex presentation in a pediatric patient with ventricular tachycardia and conduction abnormalities, harboring a\n                  <jats:italic>de novo CACNA1D<\/jats:italic>\n                  (c.3786G&gt;T) variant, and two inherited variants,\n                  <jats:italic>the SCN5A<\/jats:italic>\n                  (c.2618C&gt;G), and a\n                  <jats:italic>DSP<\/jats:italic>\n                  desmosome (c.1582C&gt;G). The\n                  <jats:italic>CACNA1D<\/jats:italic>\n                  variant, which encodes Cav1.3 L-type calcium channel is the focus of this study, because the C-terminus fragment of Cav1.3 has recently been identified as a transcription auto-enhancer of its own gene and able to prevent arrhythmic events in a mouse model of ischemic heart failure. Leveraging this intrinsic property, we hypothesized that the Cav1.3-C-terminus could reverse the arrhythmic events associated with the\n                  <jats:italic>CACNA1D<\/jats:italic>\n                  variant.\n                <\/jats:p>\n                <jats:p>\n                  Patch-clamp and optical mapping experiments demonstrated a loss of Cav1.3 function, characterized by reduced L-type calcium current densities, and decrease of conduction velocity, leading to inducible re-entrant arrhythmias in human induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs). RNA sequencing confirmed this loss-of-function via the downregulation\n                  <jats:italic>CACNA1D<\/jats:italic>\n                  gene expression.\n                <\/jats:p>\n                <jats:p>Interestingly, Cav1.3-C-terminus treatment of hiPSC-CMs successfully normalized Cav1.3 gene expression, restored calcium currents, and conduction velocity, and prevented the susceptibility to arrhythmias.<\/jats:p>\n                <jats:p>\n                  These findings highlight the electrophysiological consequences resulting from a\n                  <jats:italic>de novo<\/jats:italic>\n                  Cav1.3 variant and demonstrate an important transcriptional role of Cav1.3-C-terminus as a transcriptional regulator and as a promising therapeutic tool to restore normal electrical properties in patients with calcium channels loss of function.\n                <\/jats:p>","DOI":"10.64898\/2025.12.15.694396","type":"posted-content","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T04:55:48Z","timestamp":1766033748000},"source":"Crossref","is-referenced-by-count":3,"title":["Electrophysiological abnormalities associated with a\n                  <i>CACNA1D<\/i>\n                  variant are rescued by AAV6-Cav1.3-C-terminus gene therapy in patient-iPSC-CMs"],"prefix":"10.64898","author":[{"given":"Jean-Baptiste","family":"Reisqs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Sleiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Gando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cupelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsi Krishna Murthy","family":"Ginjupalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Delanoe-Ayari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Coetzee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxia S.","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Delmar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Cecchin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reina B.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Chahine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Boutjdir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122003150690000_2025.12.15.694396v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001209"},{"key":"2025122003150690000_2025.12.15.694396v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2010.10.012"},{"key":"2025122003150690000_2025.12.15.694396v1.3","doi-asserted-by":"publisher","DOI":"10.1172\/JCI26011"},{"key":"2025122003150690000_2025.12.15.694396v1.4","first-page":"179","article-title":"Sinus Node Dysfunction","volume":"104","year":"2021","journal-title":"afp"},{"key":"2025122003150690000_2025.12.15.694396v1.5","doi-asserted-by":"publisher","DOI":"10.31083\/j.rcm.2021.01.207"},{"key":"2025122003150690000_2025.12.15.694396v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.310230"},{"key":"2025122003150690000_2025.12.15.694396v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"2025122003150690000_2025.12.15.694396v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/wmts.102"},{"key":"2025122003150690000_2025.12.15.694396v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0935295100"},{"key":"2025122003150690000_2025.12.15.694396v1.10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.517326"},{"key":"2025122003150690000_2025.12.15.694396v1.11","doi-asserted-by":"crossref","unstructured":"Mesirca, P. , Torrente, A. 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