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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Calmodulin mutations associated with recurrent cardiac arrest in infants
Circulation, Volume 127, No. 9, Year 2013
Notification
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Description
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. © 2013 American Heart Association, Inc.
Authors & Co-Authors
CROTTI, L.
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Johnson, Christopher N.
United States, Nashville
Vanderbilt University
Graf, Elisabeth
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
De Ferrari, Gaetano Maria
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Cuneo, Bettina F.
United States, Nashville
Vanderbilt University
United States, Park Ridge
Advocate Children’s Hospital
United States, Park Ridge
Advocate Lutheran General Hospital
Ovadia, Marc
United States, Park Ridge
Advocate Lutheran General Hospital
United States, Chicago
University of Illinois at Chicago
Papagiannis, John
Greece, Athens
Mitera Children's Hospital
Feldkamp, Michael D.
United States, Nashville
Vanderbilt University
Rathi, Subodh G.
United States, Nashville
Vanderbilt University
Kunic, Jennifer D.
United States, Nashville
Vanderbilt University
Pedrazzini, Matteo
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Wieland, Thomas
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Lichtner, Peter K.
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Beckmann, B. M.
Germany, Munich
Klinikum Der Universität München
Clark, Travis
Unknown Affiliation
Shaffer, Christian M.
United States, Nashville
Center for Human Genetics Research
Benson, D. Woodrow
United States, Cincinnati
Cincinnati Children's Hospital Medical Center
United States, Milwaukee
Medical College of Wisconsin
Kääb, Stefan
Germany, Munich
Klinikum Der Universität München
Germany, Munich
Deutsches Zentrum Für Herz-kreislauf-forschung
Meitinger, Thomas A.
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Germany, Munich
Deutsches Zentrum Für Herz-kreislauf-forschung
Germany, Munich
Technische Universität München
Strom, Tim Matthias
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Germany, Munich
Technische Universität München
Chazin, Walter Jacob
United States, Nashville
Vanderbilt University
Schwartz, Peter J.
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Saudi Arabia, Riyadh
King Saud University
South Africa, Cape Town
University of Cape Town
George, Alfred L.
United States, Nashville
Vanderbilt University
United States, Nashville
Institute for Integrative Genomics
Statistics
Citations: 344
Authors: 23
Affiliations: 17
Identifiers
Doi:
10.1161/CIRCULATIONAHA.112.001216
ISSN:
00097322
e-ISSN:
15244539
Research Areas
Cancer
Genetics And Genomics
Maternal And Child Health
Noncommunicable Diseases
Study Design
Cohort Study