CALM1 – Long QT Syndrome

Autosomal dominant long QT syndrome (LQTS) type 14 is caused by heterozygous missense variants in CALM1, one of three genes encoding identical calmodulin proteins critical for cardiac excitation–contraction coupling. CALM1 mutations perturb Ca2+ binding and downstream regulation of key ion channels, leading to delayed ventricular repolarization and life-threatening arrhythmias.

Genetic Evidence

At least 12 unrelated LQTS probands have been reported with de novo CALM1 missense variants (e.g., p.Glu105Ala, p.Phe142Leu, p.Asp132Val, p.Glu141Gly) across four independent cohorts ([PMID:30937913], [PMID:28158429], [PMID:27374306], [PMID:26969752]). No familial segregation has been observed, consistent with a highly penetrant autosomal dominant mechanism with de novo occurrence.

Variant Spectrum

All pathogenic CALM1 alleles reported in LQTS are missense substitutions clustering in EF‐hand Ca2+‐binding loops. A representative allele, c.422A>G (p.Glu141Gly), reduces C-domain Ca2+ affinity by >10-fold and dominantly disrupts CaV1.2 inactivation, confirming its deleterious effect on channel regulation.

Functional Evidence

Biophysical assays demonstrate that LQTS-associated CALM1 variants markedly impair Ca2+ binding cooperativity and alter interaction with L-type Ca2+ channels and CaMKIIδ ([PMID:36496072]). In zebrafish expressing CaM-E105A, ventricular arrhythmias and tachycardia recapitulate human LQTS features ([PMID:30937913]). A Calmodulin N98S knock-in mouse exhibits QTc prolongation, sinus bradycardia, and catecholaminergic ventricular tachycardia, directly modeling human calmodulinopathy ([PMID:32929985]).

Conflicting Evidence

No conflicting genetic or functional data have emerged; rare background calmodulin variants are absent or functionally neutral in healthy cohorts.

Integration & Clinical Utility

The convergence of de novo missense CALM1 variants in unrelated LQTS patients, consistent autosomal dominant inheritance, and robust functional modeling in cellular and animal systems fulfill criteria for a Definitive gene–disease association. CALM1 should be included in comprehensive LQTS genetic testing panels, and variant interpretation guided by functional assays can inform diagnosis and management.

Key Take-home: CALM1 missense mutations cause a severe, autosomal dominant form of long QT syndrome by disrupting calmodulin’s Ca2+ sensing and channel regulation, warranting prompt genetic testing and functional validation.

References

• Circulation. Cardiovascular genetics • 2016 • Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G [PMID:26969752]
• 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]
• The Journal of Biological Chemistry • 2023 • Calmodulin variant E140G associated with long QT syndrome impairs CaMKIIδ autophosphorylation and L-type calcium channel inactivation [PMID:36496072]
• Circulation • 2020 • Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation. [PMID:32929985]

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