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

Abstract

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 CASQ2(D307H) and the CPVT phenotype using an in vivo model.

METHODS AND RESULTS:

Cardiac-specific expression of the CASQ2(D307H) transgene was achieved using the alpha-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2(D307H) 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 I(Ca)-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 CASQ2(D307H) 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.

• Authors: 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
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 75 Issue 1 Pg. 69-78 (Jul 01 2007) ISSN: 0008-6363 [Print] England
• PMID: 17449018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calsequestrin
• Cardiotonic Agents
• Caffeine
• Isoproterenol
• Calcium

Topics

• Animals
• Caffeine (pharmacology)
• Calcium (metabolism)
• Calcium Signaling
• Calsequestrin (genetics)
• Cardiotonic Agents (pharmacology)
• Death, Sudden, Cardiac (etiology)
• Electrocardiography
• Isoproterenol (pharmacology)
• Mice
• Mice, Transgenic
• Microscopy, Confocal
• Models, Animal
• Mutation, Missense
• Myocytes, Cardiac (metabolism, pathology)
• Sarcoplasmic Reticulum (metabolism)
• Tachycardia, Ventricular (genetics, metabolism, pathology)