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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)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
ISSN (print) / ISBN 1942-325X
e-ISSN 1942-3268
Zeitschrift Circulation: Cardiovascular Genetics
Quellenangaben Band: 7, Heft: 4, Seiten: 466-474 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Hagerstown, Md
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)