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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Calmodulin mutations associated with recurrent cardiac arrest in infants.
Circulation 127, 1009-1017 (2013)
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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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
ISSN (print) / ISBN
0009-7322
e-ISSN
1524-4539
Zeitschrift
Circulation
Quellenangaben
Band: 127,
Heft: 9,
Seiten: 1009-1017
Verlag
Lippincott Williams & Wilkins
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)