Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy

Michael Arad, Ivan P. Moskowitz, Vickas V. Patel, Ferhaan Ahmad, Antonio R. Perez-Atayde, Douglas B. Sawyer, Mark Walter, Guo H. Li, Patrick G. Burgon, Colin T. Maguire, David Stapleton, Joachim P. Schmitt, X. X. Guo, Anne Pizard, Sabina Kupershmidt, Dan M. Roden, Charles I. Berul, Christine E. Seidman, Jonathan G. Seidman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

282 Scopus citations


Background - Mutations in the γ2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance. Methods and Results - To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation. Conclusions - Our data establish PRKAG2 mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.

Original languageEnglish
Pages (from-to)2850-2856
Number of pages7
Issue number22
StatePublished - 10 Jun 2003
Externally publishedYes


FundersFunder number
National Heart, Lung, and Blood InstituteP01HL046681


    • Arrhythmia
    • Excitation
    • Glycogen storage disease
    • Hypertrophy
    • Kinases


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