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Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Nyegaard, Mette; Overgaard, Michael T.; Sendergaard, Mads T.; Vranas, Marta; Behr, Elijah R.; Hildebrandt, Lasse L.; Lund, Jacob; Hedley, Paula L.; Camm, A. John and Wettrell, Göran GWE LU , et al. (2012) In American Journal of Human Genetics 91(4). p.703-712
Abstract
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... (More)
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. (Less)
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American Journal of Human Genetics
volume
91
issue
4
pages
703 - 712
publisher
Cell Press
external identifiers
  • wos:000309568500012
  • scopus:84867242998
ISSN
0002-9297
DOI
10.1016/j.ajhg.2012.08.015
language
English
LU publication?
yes
id
1a49c8b0-d8ee-4676-be2a-f37a06382f99 (old id 3184276)
date added to LUP
2012-12-03 06:54:58
date last changed
2017-10-22 03:14:00
@article{1a49c8b0-d8ee-4676-be2a-f37a06382f99,
  abstract     = {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.},
  author       = {Nyegaard, Mette and Overgaard, Michael T. and Sendergaard, Mads T. and Vranas, Marta and Behr, Elijah R. and Hildebrandt, Lasse L. and Lund, Jacob and Hedley, Paula L. and Camm, A. John and Wettrell, Göran GWE and Fosdal, Inger and Christiansen, Michael and Borglum, Anders D.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {4},
  pages        = {703--712},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2012.08.015},
  volume       = {91},
  year         = {2012},
}