title: Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.
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.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark. nyegaard@hum-gen.au.dk
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.forename: Mads T
authors.initials: MT
authors.lastname: Søndergaard
authors.forename: Marta
authors.initials: M
authors.lastname: Vranas
authors.forename: Elijah R
authors.initials: ER
authors.lastname: Behr
authors.forename: Lasse L
authors.initials: LL
authors.lastname: Hildebrandt
authors.forename: Jacob
authors.initials: J
authors.lastname: Lund
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hedley
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
authors.forename: Göran
authors.initials: G
authors.lastname: Wettrell
authors.forename: Inger
authors.initials: I
authors.lastname: Fosdal
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001145:Arrhythmias, Cardiac / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics; D002147:Calmodulin / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D013575:Syncope / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000235:genetics*; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D019837:Ryanodine Receptor Calcium Release Channel