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Novel calmodulin (CALM2) mutations associated with congenital arrhythmia susceptibility.
Circ. Cardiovasc. Genet. 7, 466-474 (2014)
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DOI
PMC
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
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5.337
1.439
105
112
Anmerkungen
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
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
Sprache
englisch
Veröffentlichungsjahr
2014
HGF-Berichtsjahr
2014
ISSN (print) / ISBN
1942-325X
e-ISSN
1942-3268
Zeitschrift
Circulation: Cardiovascular Genetics
Quellenangaben
Band: 7,
Heft: 4,
Seiten: 466-474
Verlag
Lippincott Williams & Wilkins
Verlagsort
Hagerstown, Md
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)
POF Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er)
Genetics and Epidemiology
PSP-Element(e)
G-500700-001
PubMed ID
24917665
WOS ID
WOS:000341197700009
Erfassungsdatum
2014-06-13