title: 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.
  
  
  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: Department of Physiology and Cell Biology, 304 Hamilton Hall, 1645 Neil Ave, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors: Wessel P
authors: WP
authors: Dirksen
authors: Veronique A
authors: VA
authors: Lacombe
authors: Mei
authors: M
authors: Chi
authors: Anuradha
authors: A
authors: Kalyanasundaram
authors: Serge
authors: S
authors: Viatchenko-Karpinski
authors: Dmitry
authors: D
authors: Terentyev
authors: Zhixiang
authors: Z
authors: Zhou
authors: Srikanth
authors: S
authors: Vedamoorthyrao
authors: Ning
authors: N
authors: Li
authors: Nipavan
authors: N
authors: Chiamvimonvat
authors: Cynthia A
authors: CA
authors: Carnes
authors: Clara
authors: C
authors: Franzini-Armstrong
authors: Sandor
authors: S
authors: Györke
authors: Muthu
authors: M
authors: Periasamy
mesh_terms: 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
chemical_list: D002155:Calsequestrin; D002316:Cardiotonic Agents; D002110:Caffeine; D007545:Isoproterenol; D002118:Calcium