Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

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Serval ID
serval:BIB_9EDE87D756E5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Novel calmodulin mutations associated with congenital arrhythmia susceptibility.
Journal
Circulation. Cardiovascular Genetics
Author(s)
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.
ISSN
1942-3268 (Electronic)
ISSN-L
1942-3268
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
7
Number
4
Pages
466-474
Language
english
Notes
Publication types: Journal Article Publication Status: ppublish
Abstract
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 genotype-negative 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 Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
CONCLUSIONS: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
Pubmed
Web of science
Open Access
Yes
Create date
25/09/2014 17:57
Last modification date
20/08/2019 16:05
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