Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

A framework for exhaustively mapping functional missense variants

“…We applied the higher‐throughput TileSeq approach, coupled with yeast complementation, to a diverse set of genes: SUMO1, for which heterozygous null variants are associated with cleft palate (Andreou et al , 2007); thiamine pyrophosphokinase 1 (TPK1), associated with vitamin B1 metabolism dysfunction (Mayr et al , 2011); and CALM1, CALM2, and CALM3, associated with cardiac arrhythmias (long‐QT syndrome (Crotti et al , 2013) and catecholaminergic polymorphic ventricular tachycardia (Nyegaard et al , 2012)). Because the three calmodulin genes encode the same polypeptide sequence, performing DMS for CALM1 also provided maps for CALM2 and CALM3.…”

Conserved properties of individual Ca 2+ -binding sites in calmodulin

“…For instance, although CaM is essential in yeast, CaM gene knockout can be rescued with a vertebrate CaM, which is only 60% identical (62,63). Additionally, it appears that yeast can survive with Ca 2+ binding knocked out in all four EF-hands (34), whereas single mutations in just one of the three identical copies of CaM present in humans can cause major diseases (4)(5)(6). Yeast is therefore more robust to changes in CaM sequence than vertebrates, and this robustness probably translates into the higher evolutionary rate within ascomycetes.…”

“…In humans it binds to more than 300 targets (1)(2)(3). Humans have three genes that encode identical CaM proteins, but mutations in just one of the three copies can cause disease (4)(5)(6)(7)(8), as can altered gene expression (9). Although CaM has been extensively studied, many details about its function are still poorly understood.…”

Calcium-Dependent Structural Dynamics of a Spin-Labeled RyR Peptide Bound to Calmodulin

“…Several studies have shown that a disturbed CaM/RyR2 interaction plays a key role in arrhythmia and heart failure (8)(9)(10). CaM binding properties of the RyRs have focused on RyR1.…”