Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy
Michael Arad, D. Woodrow Benson, Antonio R. Perez-Atayde, William J. McKenna, Elizabeth A. Sparks, Ronald J. Kanter, Kate McGarry, J.G. Seidman, Christine E. Seidman
Michael Arad, D. Woodrow Benson, Antonio R. Perez-Atayde, William J. McKenna, Elizabeth A. Sparks, Ronald J. Kanter, Kate McGarry, J.G. Seidman, Christine E. Seidman
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Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy

Abstract

Mutations in PRKAG2, the gene for the γ2 regulatory subunit of AMP-activated protein kinase, cause cardiac hypertrophy and electrophysiologic abnormalities, particularly preexcitation (Wolff-Parkinson-White syndrome) and atrioventricular conduction block. To understand the mechanisms by which PRKAG2 defects cause disease, we defined novel mutations, characterized the associated cardiac histopathology, and studied the consequences of introducing these mutations into the yeast homologue of PRKAG2, Snf4. Although the cardiac pathology caused by PRKAG2 mutations Arg302Gln, Thr400Asn, and Asn488Ile include myocyte enlargement and minimal interstitial fibrosis, these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations. Instead PRKAG2 mutations caused pronounced vacuole formation within myocytes. Several lines of evidence indicated these vacuoles were filled with glycogen-associated granules. Analyses of the effects of human PRKAG2 mutations on Snf1/Snf4 kinase function demonstrated constitutive activity, which could foster glycogen accumulation. Taken together, our data indicate that PRKAG2 mutations do not cause hypertrophic cardiomyopathy but rather lead to a novel myocardial metabolic storage disease, in which hypertrophy, ventricular pre-excitation and conduction system defects coexist.

Authors

Michael Arad, D. Woodrow Benson, Antonio R. Perez-Atayde, William J. McKenna, Elizabeth A. Sparks, Ronald J. Kanter, Kate McGarry, J.G. Seidman, Christine E. Seidman

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Figure 1

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Identification of three PRKAG2 mutations inherited in six families and t...
Identification of three PRKAG2 mutations inherited in six families and the clinical consequences of these mutations. (a) Pedigrees indicate clinical findings of cardiac hypertrophy (left half filled), WPW (right upper quadrant filled), or conduction system disease (right lower quadrant filled) in individuals with a PRKAG2 mutation (+). Open symbols denote unaffected individuals, and shading denotes uncertain clinical status. (b) Sequence traces demonstrating G995A substitution (exon 7), C1289A (exon 11), and A1553T (exon 14), encoding Arg302Gln, Thr400Asn, and Asn488Ile substitutions, respectively. (c) Comparison of PRKAG protein sequences demonstrates evolutionary conservation of residues altered by mutation. Note that human PRKAG2 Arg302Gln mutation is homologous to R200Q mutation in RN– pigs.