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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death
American Journal of Human Genetics, Volume 91, No. 4, Year 2012
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Description
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death. © 2012 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3484646/bin/mmc1.pdf
Authors & Co-Authors
Nyegaard, Mette
Denmark, Aarhus
Aarhus Universitet
Overgaard, Michael T.
Denmark, Aalborg
Aalborg University
Sondergaard, Mads T.
Denmark, Aalborg
Aalborg University
Vranas, Marta
Denmark, Aarhus
Aarhus Universitet
Behr, Elijah R.
United Kingdom, London
St George’s, University of London
Hildebrandt, Lasse L.
Denmark, Aalborg
Aalborg University
Lund, Jacob
Denmark, Aalborg
Aalborg University
Hedley, P. L.
Denmark, Copenhagen
Statens Serum Institut
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
Camm, A. John
United Kingdom, London
St George’s, University of London
Wettrell, Göran
Sweden, Lund
Skånes Universitetssjukhus
Fosdal, Inger
Sweden, Huddinge
Visby Hospital
Christiansen, Michael
Denmark, Copenhagen
Statens Serum Institut
BØRglum, Anders Dupont
Denmark, Aarhus
Aarhus Universitet
Statistics
Citations: 13
Authors: 13
Affiliations: 7
Identifiers
Doi:
10.1016/j.ajhg.2012.08.015
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases