Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia

Marina Raffaele Di Barletta, Serge Viatchenko-Karpinski, Alessandra Nori, Mirella Memmi, Dmitry Terentyev, Federica Turcato, Giorgia Valle, Nicoletta Rizzi, Carlo Napolitano, Sandor Gyorke, Pompeo Volpe, Silvia G. Priori

Research output: Contribution to journalArticlepeer-review


BACKGROUND - Four distinct mutations in the human cardiac calsequestrin gene (CASQ2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro. METHODS AND RESULTS - We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2 did not bind Ca, whereas CASQ2 had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca-storing capacity and reduced the amplitude of ICa-induced Ca transients and of spontaneous Ca sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2. CONCLUSIONS - CASQ2 and CASQ2 alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca release and calcium content. In addition, CASQ2 displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias.

Original languageEnglish
Pages (from-to)1012-1019
Number of pages8
Issue number10
Publication statusPublished - Sep 2006


  • Calcium
  • Electrophysiology
  • Genetics
  • Tachyarrhythmias

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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