Calmodulin mutation N54I causes autosomal dominant CPVT in mice
- 1Vanderbilt University Medical Center
Abstract
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.
Related
- Extensive Parenchymal Brain Calcification in a Patient With Autosomal Dominant Polycystic Kidney Disease and Stage 5 Chronic Kidney Disease
- Customized MUC1 Sequencing Enables Diagnosis of Autosomal Dominant Tubulointerstitial Kidney Disease and Unexplained CKD
- A Case of Autosomal Dominant Alport Syndrome with Normal Type IV Collagen α5 Staining Diagnosed by a Genetic Analysis
- “A Father and Daughter Presentation of Autosomal Dominant Sleep‐Related Hypermotor Epilepsy Via a DEPDC5 Deletion in Exon 28”
- The population frequency of predicted pathogenic variants in the genes associated with Autosomal Dominant Polycystic Liver Disease (ADPLD) and kidney cysts
BibTeX
@misc{blackwell2026calmodulin,
title = {{Calmodulin mutation N54I causes autosomal dominant CPVT in mice}},
author = {D. J. Blackwell and N. Gomez Hurtado and K. Kim and P. Ritschel and C. J. Tellet Cabiya and H. He and J. R. Pinto and E. Delpire and B. C. Knollmann},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751164},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751164v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Calmodulin mutation N54I causes autosomal dominant CPVT in mice
AU - D. J. Blackwell
AU - N. Gomez Hurtado
AU - K. Kim
AU - P. Ritschel
AU - C. J. Tellet Cabiya
AU - H. He
AU - J. R. Pinto
AU - E. Delpire
AU - B. C. Knollmann
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751164
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751164v1
AB - 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.
ER -