Transgenic mice overexpressing mutant PRKAG2 define the cause of wolff-parkinson-white syndrome in glycogen storage cardiomyopathy

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-06, Vol.107 (22), p.2850-2856
• Main Authors: ARAD, Michael, MOSKOWITZ, Ivan P, STAPLETON, David, SCHMITT, Joachim P, GUO, X. X, PIZARD, Anne, KUPERSHMIDT, Sabina, RODEN, Dan M, BERUL, Charles I, SEIDMAN, Christine E, SEIDMAN, J. G, PATEL, Vickas V, AHMAD, Ferhaan, PEREZ-ATAYDE, Antonio R, SAWYER, Douglas B, WALTER, Mark, LI, Guo H, BURGON, Patrick G, MAGUIRE, Colin T
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases; Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiomyopathies - complications; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Disease Models, Animal; Electrocardiography; Electrophysiologic Techniques, Cardiac; Glycogen Storage Disease - complications; Glycogen Storage Disease - pathology; Glycogen Storage Disease - physiopathology; Heart; Heart Conduction System - physiopathology; Humans; Medical sciences; Mice; Mice, Transgenic; Multienzyme Complexes - biosynthesis; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Mutation; Myocarditis. Cardiomyopathies; Myocardium - pathology; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Survival Rate; Wolff-Parkinson-White Syndrome - etiology; Wolff-Parkinson-White Syndrome - pathology; Wolff-Parkinson-White Syndrome - physiopathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000075270.13497.2B

Mutations in the gamma2 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. 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. 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.