Calmodulinopathy: A Novel, Life-Threatening Clinical Entity Affecting the Young

Abstract

Sudden cardiac death (SCD) in the young may often be the first manifestation of a genetic arrythmogenic disease that had remained undiagnosed. Despite the significant discoveries of the genetic bases of inherited arrhythmia syndromes, there remains a measurable fraction of cases where in-depth clinical and genetic investigations fail to identify the underlying SCD etiology. A few years ago, 2 cases of infants with recurrent cardiac arrest episodes, due to what appeared to be as a severe form of long QT syndrome (LQTS), came to our attention. These prompted a number of clinical and genetic research investigations that allowed us to identify a novel, closely associated to LQTS but nevertheless distinct, clinical entity that is now known as calmodulinopathy. Calmodulinopathy is a life-threatening arrhythmia syndrome, affecting mostly young individuals, caused by mutations in any of the 3 genes encoding calmodulin (CaM). Calmodulin is a ubiquitously expressed Ca²⁺ signaling protein that, in the heart, modulates several ion channels and participates in a plethora of cellular processes. We will hereby provide an overview of CaM's structure and function under normal and disease states, highlighting the genetic etiology of calmodulinopathy and the related disease mechanisms. We will also discuss the phenotypic spectrum of patients with calmodulinopathy and present state-of-the art approaches with patient-derived induced pluripotent stem cells that have been thus far adopted in order to accurately model calmodulinopathy in vitro, decipher disease mechanisms and identify novel therapies.

Keywords: CALM; calmodulin; catecholaminergic polymorphic ventricular tachycardia; long QT syndrome; sudden cardiac death.

Figure 1

(A) Multiple species alignment of the CaM protein sequence showing full sequence conservation across vertebrates and an impressive sequence conservation across lower eukaryotes. (B) CaM protein structure in the ApoCaM (left) and Holo- or CaCaM conformation (right). The N-terminal and C-terminal Ca²⁺ lobes are shown in blue and red, respectively. Ca²⁺ ions are shown in yellow. PDB structures entries: ApoCaM PDB ID: 1CFD; CaCaM PDB ID: 1CLL. (C) Genotype-phenotype correlation graphic representation of published CaM mutations, with respect to the gene and domain in which the mutations reside. C-terminal Ca²⁺-binding domains are shown in red and N-terminal Ca²⁺-binding domains are shown in blue.

Figure 2

(A) LQTS-CaMs induce an increased Ca²⁺ influx via I_CaL by decreasing its Ca²⁺-dependent inactivation (CDI); this causes an enhanced Ca²⁺ influx, a consequent action potential duration (APD) prolongation and arrhythmias. LTCC: L-type calcium channels. (B) CPVT-CaMs promote Ca²⁺-release from the sarcoplasmic reticulum through the cardiac ryanodine receptors (RyR2). This leads to a higher frequency of Ca²⁺ waves and to a higher arrhythmia susceptibility, especially in the presence of catecholamines.

Figure 3

Graphic representation depicting a theory to explain the strong phenotypic effect and allelic dominance of CaM mutants in the setting of heterozygous LQTS-CaM mutations. The lower Ca²⁺ binding affinity of LQTS-CaMs creates a larger than expected pool of LQTS-ApoCaMs, i.e., the conformation that binds LTCCs, with a consequent higher-than-expected abundance of LQTS-CaM bound to LTCCs. Thus, LTCCs will have a high percentage of dysfunctional CaMs bound, which will significantly disrupt their activity despite the 5:1 WT:MT allelic stoichiometry.