CALM3

CALM3 encodes calmodulin, a highly conserved calcium-binding messenger protein that functions as a central regulator of calcium signal transduction and controls diverse targets including ion channels and signaling enzymes through calcium-dependent interactions^[1][2]. Mechanistically, CALM3-derived calmodulin participates in the regulation of cardiac calcium handling and excitation-contraction coupling, processes that are essential for electrical stability and normal heart rhythm^[3][4]. Pathogenic variants in calmodulin genes disrupt calcium-dependent regulation of ion channels, and calmodulin mutations associated with long QT syndrome impair inactivation of cardiac L-type Ca²⁺ currents and promote proarrhythmic cellular behavior^[5][6]. Accordingly, CALM3 variants have been linked to severe inherited arrhythmia phenotypes, including pediatric long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, establishing CALM3 as a disease-relevant component of calmodulinopathy models^[4][7][8]. Compared with the related isoforms encoded by CALM1 and CALM2, CALM3 produces an identical calmodulin protein but exhibits distinct gene-specific expression, translational efficiency, and clinical consequences of missense variants, highlighting the importance of isoform-aware interpretation in mechanistic and translational studies^[9]. Recent analyses indicate that CALM3 contributes a smaller fraction of ventricular calmodulin production than CALM1 and CALM2, which may partially explain differences in disease severity among calmodulinopathy patients carrying variants in different calmodulin genes^[9]. For experimental applications, naturally occurring CALM3 mutations provide valuable models for investigating calcium-signaling defects, arrhythmogenic mechanisms, and genotype-phenotype relationships in inherited cardiac disorders^[4][8].

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