title: Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome.
abstract: BACKGROUND
  We identified a gene (PRKAG2) that encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy.
  
  
  RESULTS
  To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TG(WT)) and mutant(TG(R302Q)) PRKAG2 gene with the cardiac-specific promoter alpha-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG(R302Q) mice to have ventricular preexcitation (PR interval 10+/-2 versus 33+/-5 ms in TG(WT), P<0.05) and a prolonged QRS (20+/-5 versus 10+/-1 ms in TG(WT), P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TG(WT)) and ventricular wall thickness.
  
  
  CONCLUSIONS
  We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.
authors.affiliation: Baylor College of Medicine,Houston, Tex, USA.
authors.forename: Jasvinder S
authors.initials: JS
authors.lastname: Sidhu
authors.forename: Yadavendra S
authors.initials: YS
authors.lastname: Rajawat
authors.forename: Tapan G
authors.initials: TG
authors.lastname: Rami
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
authors.forename: Zhinong
authors.initials: Z
authors.lastname: Wang
authors.forename: Ruiyong
authors.initials: R
authors.lastname: Yuan
authors.forename: A J
authors.initials: AJ
authors.lastname: Marian
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Donald
authors.initials: D
authors.lastname: Weilbacher
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Davies
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Dirar S
authors.initials: DS
authors.lastname: Khoury
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
mesh_terms: D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002304:Cardiac Pacing, Artificial; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology; D018995:Myosin Heavy Chains / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013611:Tachycardia, Atrioventricular Nodal Reentry / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D014927:Wolff-Parkinson-White Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology
chemical_list: D009097:Multienzyme Complexes; D000249:Adenosine Monophosphate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D018995:Myosin Heavy Chains