PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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)
Verlagsversion Volltext DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
15.202
4.529
224
229
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Zeitschrift Circulation
Quellenangaben Band: 127, Heft: 9, Seiten: 1009-1017 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
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 23388215
DOI 10.1161/CIRCULATIONAHA.112.001216
WOS ID WOS:000315804800015
Scopus ID 84874664698
Erfassungsdatum 2013-04-04
[➜Korrektur melden]