Published online before print June 2, 2003, doi: 10.1161/01.CIR.0000075270.13497.2B
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(Circulation. 2003;107:2850.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Transgenic Mice Overexpressing Mutant PRKAG2 Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy
From the Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute (M.A., I.P.M., F.A., G.H.L., P.G.B., J.P.S., A.P., C.E.S., J.G.S.), the Department of Pathology and Cardiac Registry, Children’s Hospital, and Harvard Medical School (I.P.M., A.R.P.-A.), the Department of Cardiology, Children’s Hospital and Department of Pediatrics, Harvard Medical School (V.V.P., C.T.M., C.I.B.), Boston University Medical Center, Myocardial Biology Unit (D.B.S., X.X.G.), and the Division of Cardiology, Brigham and Women’s Hospital (C.E.S.), Boston, Mass; the Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia (V.V.P.); St Vincent’s Institute of Medical Research, Victoria, Australia (M.W., D.S.); and the Departments of Anesthesiology and Pharmacology (S.K.) and Medicine, Pharmacology, Molecular Physiology, and Biophysics (D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Jonathan Seidman, PhD, Department of Genetics, Alpert Room 533, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115. E-mail seidman{at}rascal.med.harvard.edu
Background— Mutations in the 
2 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.
Key Words: kinases • glycogen storage disease • excitation • arrhythmia • hypertrophy
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