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Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy

Publication ,  Journal Article
Arad, M; Woodrow Benson, D; Perez-Atayde, AR; McKenna, WJ; Sparks, EA; Kanter, RJ; McGarry, K; Seidman, JG; Seidman, CE
Published in: Journal of Clinical Investigation
January 1, 2002

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.

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Published In

Journal of Clinical Investigation

DOI

ISSN

0021-9738

Publication Date

January 1, 2002

Volume

109

Issue

3

Start / End Page

357 / 362

Related Subject Headings

  • Immunology
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences
 

Citation

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Arad, M., Woodrow Benson, D., Perez-Atayde, A. R., McKenna, W. J., Sparks, E. A., Kanter, R. J., … Seidman, C. E. (2002). Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Journal of Clinical Investigation, 109(3), 357–362. https://doi.org/10.1172/JCI0214571
Arad, M., D. Woodrow Benson, A. R. Perez-Atayde, W. J. McKenna, E. A. Sparks, R. J. Kanter, K. McGarry, J. G. Seidman, and C. E. Seidman. “Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy.” Journal of Clinical Investigation 109, no. 3 (January 1, 2002): 357–62. https://doi.org/10.1172/JCI0214571.
Arad M, Woodrow Benson D, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Journal of Clinical Investigation. 2002 Jan 1;109(3):357–62.
Arad, M., et al. “Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy.” Journal of Clinical Investigation, vol. 109, no. 3, Jan. 2002, pp. 357–62. Scopus, doi:10.1172/JCI0214571.
Arad M, Woodrow Benson D, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Journal of Clinical Investigation. 2002 Jan 1;109(3):357–362.

Published In

Journal of Clinical Investigation

DOI

ISSN

0021-9738

Publication Date

January 1, 2002

Volume

109

Issue

3

Start / End Page

357 / 362

Related Subject Headings

  • Immunology
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences