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Makita, N.* ; Yagihara, N.* ; Crotti, L. ; Johnson, C.N.* ; Beckmann, B.M.* ; Roh, M.S.* ; Shigemizu, D.* ; Lichtner, P. ; Ishikawa, T.* ; Aiba, T.* ; Homfray, T.* ; Behr, E.R.* ; Klug, D.* ; Denjoy, I.* ; Mastantuono, E. ; Theisen, D.* ; Tsunoda, T.* ; Satake, W.* ; Toda, T.* ; Nakagawa, H.* ; Tsuji, Y.* ; Tsuchiya, T.* ; Yamamoto, H.* ; Miyamoto, Y.* ; Endo, N.* ; Kimura, A.* ; Ozaki, K.* ; Motomura, H.* ; Suda, K.* ; Tanaka, T.* ; Schwartz, P.J.* ; Meitinger, T. ; Kääb, S.* ; Guicheney, P.* ; Shimizu, W.* ; Bhuiyan, Z.A.* ; Watanabe, H.* ; Chazin, W.J.* ; George, A.L.*

Novel calmodulin (CALM2) mutations associated with congenital arrhythmia susceptibility.

Circ. Cardiovasc. Genet. 7, 466-474 (2014)
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BACKGROUND: -Genetic predisposition to life-threatening cardiac arrhythmias such as in 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 employed conventional and next-generation sequencing approaches including exome analysis in genotype-negative LQTS probands. We identified five novel de novo missense mutations in CALM2 in three subjects with LQTS (p.N98S, p.N98I, p.D134H) and two 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 1-9 years. Three of five probands had cardiac arrest and one of these subjects did not survive. Although all probands had LQTS, two subjects also exhibited electrocardiographic features consistent with CPVT. 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 five probands responded to β-blocker therapy whereas one subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within calcium binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced calcium binding affinity. CONCLUSIONS: -CALM2M mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calmodulin ; Genetics ; Long Qt Syndrome ; Ventricular Arrhythmia; Long-qt Syndrome; Polymorphic Ventricular-tachycardia; Sudden Cardiac Death; T-wave Patterns; Calcium-binding; Ryanodine Receptor; Whole-genome; Sequencing Data; Ca2+ Release; Genotype
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 1942-325X
e-ISSN 1942-3268
Journal Circulation: Cardiovascular Genetics
Quellenangaben Volume: 7, Issue: 4, Pages: 466-474 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Hagerstown, Md
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 24917665
DOI 10.1161/CIRCGENETICS.113.000459
WOS ID WOS:000341197700009
Erfassungsdatum 2014-06-13
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