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Crotti, L. ; Johnson, C.N.* ; Graf, E. ; de Ferrari, G.M.* ; Cuneo, B.F.* ; Ovadia, M.* ; Papagiannis, J.* ; Feldkamp, M.D.* ; Rathi, S.G.* ; Kunic, J.D.* ; Pedrazzini, M.* ; Wieland, T. ; Lichtner, P. ; Beckmann, B.M.* ; Clark, T.* ; Shaffer, C.* ; Benson, D.W.* ; Kääb, S.* ; Meitinger, T. ; Strom, T.M. ; Chazin, W.J.* ; Schwartz, P.J.* ; George, A.L.*

Calmodulin mutations associated with recurrent cardiac arrest in infants.

Circulation 127, 1009-1017 (2013)
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Background-Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results-We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions-Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Arrhythmia ; Calcium Signaling ; Death, Sudden, Cardiac ; Exome; Long-qt Syndrome ; Sodium-channel ; Death-syndrome ; Calcium-binding ; Apo-calmodulin ; Sensor Proteins ; Ca2+ Sensor ; Inactivation ; Domains ; Variant
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Journal Circulation
Quellenangaben Volume: 127, Issue: 9, Pages: 1009-1017 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
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 23388215
DOI 10.1161/CIRCULATIONAHA.112.001216
WOS ID WOS:000315804800015
Scopus ID 84874664698
Erfassungsdatum 2013-04-04
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