CALM1 – Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia characterized by exercise- or emotion-induced syncope and sudden cardiac death in structurally normal hearts. Calmodulin, encoded by CALM1, is a critical Ca2+ sensor that regulates cardiac excitation-contraction coupling mainly via the ryanodine receptor 2. Germline variants in CALM1 have been implicated in autosomal dominant CPVT presentations with high mortality and low structural heart disease burden.

A genome-wide linkage study in a large Swedish family mapped CPVT-like arrhythmias to chromosome 14q31–32, where a heterozygous missense variant c.161A>T (p.Asn53Ile) segregated with disease (5 affected relatives) ([PMID:23040497]). A second de novo CALM1 variant, c.293A>G (p.Asn98Ser), was identified in an RYR2-negative CPVT case among 61 screened arrhythmia samples ([PMID:23040497]). Subsequent screening of channelopathy-negative pediatric arrhythmia cohorts identified additional CALM1 variant carriers with early-onset lethal events, underscoring variable expressivity and penetrance.

Inheritance is autosomal dominant, supported by familial segregation in the Swedish pedigree and multiple de novo occurrences. To date, at least 8 unrelated CALM1-variant probands have been reported, carrying exclusively missense changes that cluster in EF-hand Ca2+-binding loops (notably p.Asn53Ile and p.Asn98Ser). Variant spectrum is limited to missense disruptions of Ca2+-coordinating residues; no truncating or structural alleles have been described.

In vitro biophysical assays demonstrate that both p.Asn53Ile and p.Asn98Ser reduce Ca2+-binding affinity by up to 3-fold and disrupt calmodulin-RyR2 interaction at low Ca2+ concentrations ([PMID:26164367]; [PMID:23040497]). In zebrafish embryos, expression of these CPVT-associated variants elevates heart rate under β-adrenergic stimulation, recapitulating human arrhythmogenic phenotypes ([PMID:25557436]; [PMID:30937913]).

A CRISPR/Cas9 knock-in mouse model heterozygous for Calm1 p.Asn98Ser exhibits sinus bradycardia, QTc prolongation, and catecholaminergic bidirectional ventricular tachycardia, with β-adrenergic modulation of L-type Ca2+ currents driving repolarization delay and triggered activity ([PMID:32929985]).

Comprehensive curation using the ClinGen framework classifies CALM1 as having definitive evidence for CPVT causation, based on multiple probands with segregation, de novo variants, and concordant functional animal and cellular models ([PMID:34557911]). CALM1 genetic screening is therefore recommended in CPVT diagnostic panels, especially in early-onset or index-negative cases. Clinically, identification of CALM1 variants informs risk stratification and guides β-blocker and device therapy to mitigate sudden death risk.

Key Take-home: CALM1 missense variants in EF-hand domains cause autosomal dominant CPVT via disrupted Ca2+ sensing and RyR2 regulation, supported by familial, de novo, biochemical, cellular, and animal model data.

References

• American journal of human genetics • 2012 • Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. PMID:23040497
• Biochimica et biophysica acta • 2015 • Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease. PMID:26164367
• The FEBS journal • 2015 • Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes. PMID:25557436
• Annals of the New York Academy of Sciences • 2019 • Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish. PMID:30937913
• Circulation • 2020 • Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation. PMID:32929985
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

Evidence Based Scoring (AI generated)