Key result
Heterozygous N54I calmodulin expression provokes spontaneous calcium release and catecholamine-induced ventricular arrhythmias in mice.
Why the study?
Pathogenic calmodulin variants are expressed in a small fraction of total cellular calmodulin, raising uncertainty whether this limited abundance is sufficient to produce an arrhythmogenic phenotype in vivo.
Expression of the N54I calmodulin mutation from a single Calm1 allele, despite constituting only 13.7% of total cardiac CaM, is sufficient to produce a clinically relevant CPVT phenotype in vivo, demonstrating functional dominance.
Answers are grounded in this paper and cite their sources.
Supports dominant arrhythmogenic effect of heterozygous CALM1-N54I in mice; hypothesis-generating for human calmodulinopathy mechanisms.
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 RYR2 and CASQ2 account for most genetically defined cases, although pathogenic variants in the three genes encoding calmodulin ( CALM1–3 ) have also been linked to CPVT. Because all three CALM 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 Calm1 . Mutant calmodulin accounted for 13.7% of total cardiac calmodulin, consistent with expression from one of six Calm 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 Calm1 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. One Sentence Summary A single CALM1 N54I allele causes catecholaminergic polymorphic ventricular tachycardia in mice
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Blackwell et al. (2026) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT). Calm1 N54I mutation vs. Wild-type littermates was evaluated on Catecholamine-induced ventricular arrhythmias. Expression of the N54I calmodulin variant from a single endogenous Calm1 allele is sufficient to provoke spontaneous calcium release and catecholamine-induced ventricular arrhythmias in mice.
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