{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:05Z","timestamp":1792790405812,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,18]]},"group-title":"Physiology","reference-count":18,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NHLBI","award":["R01HL183508"],"award-info":[{"award-number":["R01HL183508"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NHLBI","award":["R01HL177564"],"award-info":[{"award-number":["R01HL177564"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NHLBI","award":["R01HL160966"],"award-info":[{"award-number":["R01HL160966"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NHLBI","award":["R01HL179825"],"award-info":[{"award-number":["R01HL179825"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by stress- or catecholamine-induced ventricular arrhythmias in the absence of overt structural heart disease. Mutations in\n                  <jats:italic>RYR2<\/jats:italic>\n                  and\n                  <jats:italic>CASQ2<\/jats:italic>\n                  account for most genetically defined cases, although pathogenic variants in the three genes encoding calmodulin (\n                  <jats:italic>CALM1\u20133<\/jats:italic>\n                  ) have also been linked to CPVT. Because all three\n                  <jats:italic>CALM<\/jats:italic>\n                  genes encode an identical calmodulin protein, pathogenic calmodulin variants are expected to be expressed in only a small fraction of total cellular calmodulin, raising the question of whether this limited abundance is sufficient to produce an arrhythmogenic phenotype in vivo. We generated a heterozygous mouse model carrying the human disease-associated N54I-equivalent mutation, N54I, in\n                  <jats:italic>Calm1<\/jats:italic>\n                  . Mutant calmodulin accounted for 13.7% of total cardiac calmodulin, consistent with expression from one of six\n                  <jats:italic>Calm<\/jats:italic>\n                  alleles. Under basal conditions, N54I\/+ mice exhibited normal growth, survival, cardiac morphology, and surface electrocardiogram parameters. However, cardiomyocytes isolated from N54I\/+ mice had increased rates of RyR2-mediated spontaneous calcium release. Following catecholaminergic challenge with isoproterenol and caffeine, N54I\/+ mice exhibited significantly more premature ventricular contractions and arrhythmias than wild-type littermates. Exercise challenge in conscious mice similarly provoked ventricular ectopy and ventricular tachycardia. In addition, N54I\/+ mice exhibited abnormalities of atrial and sinoatrial electrical activity, including premature atrial contractions, ectopic P waves, atrioventricular conduction slowing, and beat-to-beat variability. These findings demonstrate that expression of the N54I calmodulin variant from a single\n                  <jats:italic>Calm1<\/jats:italic>\n                  allele is sufficient to produce a CPVT phenotype in vivo. This model provides experimental evidence linking a human disease-associated calmodulin variant to arrhythmogenesis and demonstrates the functional dominance of mutant calmodulin in the heart.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>A single CALM1 N54I allele causes catecholaminergic polymorphic ventricular tachycardia in mice<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.12.751164","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:30:12Z","timestamp":1789759812000},"source":"Crossref","is-referenced-by-count":0,"title":["Calmodulin mutation N54I causes autosomal dominant CPVT in mice"],"prefix":"10.64898","author":[{"given":"Daniel J.","family":"Blackwell","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Gomez-Hurtado","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paxton A.","family":"Ritschel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Tellet-Cabiya","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"He","sequence":"additional","affiliation":[{"name":"Translational Science Laboratory, College of Medicine, Florida State University, Tallahassee, FL"},{"name":"Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose R.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Delpire","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":false,"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville 37235, Tennessee, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092208550552000_2026.09.12.751164v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00682-7"},{"key":"2026092208550552000_2026.09.12.751164v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.06.005"},{"key":"2026092208550552000_2026.09.12.751164v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"2026092208550552000_2026.09.12.751164v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.015"},{"key":"2026092208550552000_2026.09.12.751164v1.5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.001216"},{"key":"2026092208550552000_2026.09.12.751164v1.6","first-page":"A17783","article-title":"Abstract 17783: Calmodulin Mutants Associated With Long 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