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


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.
Dirksen
Wessel P
WP
Department of Physiology and Cell Biology, 304 Hamilton Hall, 1645 Neil Ave, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Lacombe
Veronique A
VA
Chi
Mei
M
Kalyanasundaram
Anuradha
A
Viatchenko-Karpinski
Serge
S
Terentyev
Dmitry
D
Zhou
Zhixiang
Z
Vedamoorthyrao
Srikanth
S
Li
Ning
N
Chiamvimonvat
Nipavan
N
Carnes
Cynthia A
CA
Franzini-Armstrong
Clara
C
Györke
Sandor
S
Periasamy
Muthu
M
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002155:Calsequestrin / Q000235:genetics*; D002316:Cardiotonic Agents / Q000494:pharmacology; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D023421:Models, Animal; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D002155:Calsequestrin; D002316:Cardiotonic Agents; D002110:Caffeine; D007545:Isoproterenol; D002118:Calcium