title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families. The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons. Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2. One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years. Despite the different mutations, there is little phenotypic variation of CPVT for the CASQ2 mutations. Of the 16 heterozygous carriers of these various mutations, 14 were devoid of clinical symptoms or ECG anomalies, whereas 2 of them had ventricular arrhythmias at ECG on exercise tests. In line with this, the diagnosis of the probands was difficult because of the absence of a positive family history. In conclusion, these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT. The full text of this article is available at http://www.circresaha.org.
authors.affiliation: INSERM U523, Institut de Myologie, IFR Coeur, muscles et vaisseaux No. 14, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Alex V
authors.initials: AV
authors.lastname: Postma
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Theo M
authors.initials: TM
authors.lastname: Hoorntje
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lupoglazoff
authors.forename: Antoine
authors.initials: A
authors.lastname: Da Costa
authors.forename: Pascale
authors.initials: P
authors.lastname: Sebillon
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000293:Adolescent; D000328:Adult; D002155:Calsequestrin / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010375:Pedigree; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics*
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D018389:Codon, Nonsense