Novel calmodulin mutations associated with congenital arrhythmia susceptibility

Naomasa Makita*, Nobue Yagihara, Lia Crotti, Christopher N. Johnson, Britt Maria Beckmann, Michelle S. Roh, Daichi Shigemizu, Peter Lichtner, Taisuke Ishikawa, Takeshi Aiba, Tessa Homfray, Elijah R. Behr, Didier Klug, Isabelle Denjoy, Elisa Mastantuono, Daniel Theisen, Tatsuhiko Tsunoda, Wataru Satake, Tatsushi Toda, Hidewaki NakagawaYukiomi Tsuji, Takeshi Tsuchiya, Hirokazu Yamamoto, Yoshihiro Miyamoto, Naoto Endo, Akinori Kimura, Kouichi Ozaki, Hideki Motomura, Kenji Suda, Toshihiro Tanaka, Peter J. Schwartz, Thomas Meitinger, Stefan Kääb, Pascale Guicheney, Wataru Shimizu, Zahurul A. Bhuiyan, Hiroshi Watanabe, Walter J. Chazin, Alfred L. George

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


Background: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. Methods and Results: We used conventional and next-generation sequencing approaches, including exome analysis, in genotypenegative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca2+-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca2+-binding affinity. Conclusions: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT..

Original languageEnglish (US)
Pages (from-to)466-474
Number of pages9
JournalCirculation: Cardiovascular Genetics
Issue number4
StatePublished - Aug 1 2014


  • Calmodulin
  • Long QT syndrome

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)


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