RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Sidhu, JS  Rajawat, YS  Rami, TG  Gollob, MH  Wang, Z  Yuan, R  Marian, AJ  DeMayo, FJ  Weilbacher, D  Taffet, GE  Davies, JK  Carling, D  Khoury, DS  Roberts, R 
Citation: Sidhu JS, etal., Circulation. 2005 Jan 4;111(1):21-9. Epub 2004 Dec 20.
RGD ID: 1580718
Pubmed: PMID:15611370   (View Abstract at PubMed)
PMCID: PMC2908313   (View Article at PubMed Central)
DOI: DOI:10.1161/01.CIR.0000151291.32974.D5   (Journal Full-text)

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. METHODS AND 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Wolff-Parkinson-White syndrome  IMP 1580718 RGD 
Wolff-Parkinson-White syndrome  ISOPRKAG2 (Homo sapiens)1580718; 1580718 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Prkag2  (protein kinase AMP-activated non-catalytic subunit gamma 2)

Genes (Mus musculus)
Prkag2  (protein kinase, AMP-activated, gamma 2 non-catalytic subunit)

Genes (Homo sapiens)
PRKAG2  (protein kinase AMP-activated non-catalytic subunit gamma 2)


Additional Information