Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death

Mette Nyegaard, Michael Toft Overgaard, M.T. Sondergaard, Marta Vranas, Elijah R. Behr, L.L. Hildebrandt, J. Lund, Paula L. Hedley, A. John Camm, Göran Wettrell, Inger Fosdal, Michael Christiansen, Anders D. Borglum

Research output: Contribution to journalJournal articleResearchpeer-review

316 Citations (Scopus)

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.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume91
Issue number4
Pages (from-to)703-712
Number of pages10
ISSN0002-9297
DOIs
Publication statusPublished - 2012

Bibliographical note

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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