A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice

Wessel P. Dirksen, Veronique A. Lacombe, Mei Chi, Anuradha Kalyanasundaram, Serge Viatchenko-Karpinski, Dmitry Terentyev, Zhixiang Zhou, Srikanth Vedamoorthyrao, Ning Li, Nipavan Chiamvimonvat, Cynthia A. Carnes, Clara Franzini-Armstrong, Sandor Györke, Muthu Periasamy

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Objective: A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2D307H and the CPVT phenotype using an in vivo model. Methods and results: Cardiac-specific expression of the CASQ2D307H transgene was achieved using the α-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2D307H from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished ICa-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia. Conclusions: The findings of the present study demonstrate that expression of mutant CASQ2D307H in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalCardiovascular Research
Issue number1
StatePublished - Jul 1 2007

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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