Calmodulinopathy

Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes

Beatrice Badone, Carlotta Ronchi, Maria-Christina Kotta, Luca Sala, Alice Ghidoni, Lia Crotti, Antonio Zaza

Research output: Contribution to journalReview article

Abstract

In spite of the widespread role of calmodulin (CaM) in cellular signaling, CaM mutations lead specifically to cardiac manifestations, characterized by remarkable electrical instability and a high incidence of sudden death at young age. Penetrance of the mutations is surprisingly high, thus postulating a high degree of functional dominance. According to the clinical patterns, arrhythmogenesis in CaM mutations can be attributed, in the majority of cases, to either prolonged repolarization (as in long-QT syndrome, LQTS phenotype), or to instability of the intracellular Ca2+ store (as in catecholamine-induced tachycardias, CPVT phenotype). This review discusses how mutations affect CaM signaling function and how this may relate to the distinct arrhythmia phenotypes/mechanisms observed in patients; this involves mechanistic interpretation of negative dominance and mutation-specific CaM-target interactions. Knowledge of the mechanisms involved may allow critical approach to clinical manifestations and aid in the development of therapeutic strategies for "calmodulinopathies," a recently identified nosological entity.

Original languageEnglish
Pages (from-to)176
JournalFrontiers in cardiovascular medicine
Volume5
DOIs
Publication statusPublished - 2018

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Calmodulin
Phenotype
Mutation
Long QT Syndrome
Penetrance
Sudden Death
Tachycardia
Catecholamines
Cardiac Arrhythmias
Incidence

Cite this

Calmodulinopathy : Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes. / Badone, Beatrice; Ronchi, Carlotta; Kotta, Maria-Christina; Sala, Luca; Ghidoni, Alice; Crotti, Lia; Zaza, Antonio.

In: Frontiers in cardiovascular medicine, Vol. 5, 2018, p. 176.

Research output: Contribution to journalReview article

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AU - Ghidoni, Alice

AU - Crotti, Lia

AU - Zaza, Antonio

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AB - In spite of the widespread role of calmodulin (CaM) in cellular signaling, CaM mutations lead specifically to cardiac manifestations, characterized by remarkable electrical instability and a high incidence of sudden death at young age. Penetrance of the mutations is surprisingly high, thus postulating a high degree of functional dominance. According to the clinical patterns, arrhythmogenesis in CaM mutations can be attributed, in the majority of cases, to either prolonged repolarization (as in long-QT syndrome, LQTS phenotype), or to instability of the intracellular Ca2+ store (as in catecholamine-induced tachycardias, CPVT phenotype). This review discusses how mutations affect CaM signaling function and how this may relate to the distinct arrhythmia phenotypes/mechanisms observed in patients; this involves mechanistic interpretation of negative dominance and mutation-specific CaM-target interactions. Knowledge of the mechanisms involved may allow critical approach to clinical manifestations and aid in the development of therapeutic strategies for "calmodulinopathies," a recently identified nosological entity.

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