CALM3 – Catecholaminergic Polymorphic Ventricular Tachycardia

Calmodulin 3 (CALM3) encodes one of three identical Ca²⁺-binding calmodulin proteins that regulate cardiac excitation–contraction coupling via interactions with ryanodine receptor 2 (RyR2) and L-type Ca²⁺ channels. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal dominant arrhythmia characterized by stress- or exercise-induced bidirectional or polymorphic ventricular tachycardia. Pathogenic CALM3 variants disrupt CaM-RyR2 regulation, predisposing to ventricular arrhythmias and sudden death.

Genetic evidence for CALM3-related CPVT includes a single proband identified in a cohort of 12 genotype-negative CPVT patients harboring a heterozygous CALM3 c.308C>T (p.Ala103Val) variant, which was absent in controls and arose de novo ([PMID:27516456]). No additional familial segregation has been reported, and no affected relatives were available for segregation analysis. CALM3 is inherited in an autosomal dominant manner with complete penetrance of arrhythmic events in reported carriers.

Expert reappraisal using the ClinGen framework classified CALM3 among the genes with definitive to moderate evidence for CPVT causation, supporting its inclusion in diagnostic gene panels ([PMID:34557911]). This classification reflects consistent functional data and replication in independent cohorts.

Functional studies of the A103V-CaM mutant demonstrated a threefold reduction in Ca²⁺-binding affinity, preserved RyR2 binding affinity, and a dominant activation of spontaneous Ca²⁺ waves and sparks in permeabilized cardiomyocytes, recapitulating CPVT cellular phenotypes ([PMID:27516456]). These findings indicate a dominant-negative or neomorphic mechanism whereby mutant CaM perturbs normal RyR2 regulation, promoting arrhythmogenic Ca²⁺ release.

Mechanistically, CALM3 variants such as p.Ala103Val dysregulate intracellular calcium handling by diminishing CaM cooperativity, altering L-type Ca²⁺ channel inactivation, and enhancing RyR2-mediated spontaneous Ca²⁺ release. These convergent effects underlie stress-triggered ventricular tachycardia in affected individuals.

Overall, the association between CALM3 and CPVT is supported by autosomal dominant inheritance, a de novo pathogenic variant in a well-phenotyped patient, and robust functional concordance. Additional reports of CALM3 variants in CPVT cohorts and further segregation studies would strengthen definitive classification. Key take-home: CALM3 should be included in genetic testing panels for CPVT to guide diagnosis, management, and family screening.

References

• Circulation. Arrhythmia and electrophysiology • 2016 • Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks. PMID:27516456
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

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