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Gene Review

PRKAG2  -  protein kinase, AMP-activated, gamma 2 non...

Homo sapiens

Synonyms: 5'-AMP-activated protein kinase subunit gamma-2, AAKG, AAKG2, AMPK gamma2, AMPK subunit gamma-2, ...
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Disease relevance of PRKAG2

  • Mutations in PRKAG2, the gene for the gamma 2 regulatory subunit of AMP-activated protein kinase, cause cardiac hypertrophy and electrophysiologic abnormalities, particularly preexcitation (Wolff-Parkinson-White syndrome) and atrioventricular conduction block [1].
  • 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 [1].
  • 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 [1].
  • OBJECTIVES: The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM) [2].
  • Mutations in PRKAG2 appear to specifically cause HCM with WPW and conduction disease, and not other inherited cardiomyopathies [3].

High impact information on PRKAG2

  • We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2) [4].
  • Instead PRKAG2 mutations caused pronounced vacuole formation within myocytes [1].
  • Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous [5].
  • R531Q and other PRKAG2 mutations enhance the basal activity and alpha -subunit phosphorylation of AMP-activated protein kinase, explaining the dominant nature of PRKAG2 disease mutations [5].
  • CONCLUSIONS: Transgenic mice overexpressing the Asn488Ile PRKAG2 mutation recapitulate an electrophysiologic phenotype similar to humans with this mutation [6].

Chemical compound and disease context of PRKAG2

  • The perturbation of AMPK activity induced by genetic mutations in PRKAG2 and the resultant effect on muscle cell glucose metabolism may be relevant to the issue of targeting AMPK in drug development for insulin-resistant diabetes mellitus [7].

Biological context of PRKAG2

  • The PRKAG2 gene was located to human chromosome 7q36 between markers D7S2439 and D7S2462 by radiation hybrid mapping [8].
  • We have recently shown that HCM associated with Wolff-Parkinson-White syndrome (WPW) and conduction disease can be caused by mutations in PRKAG2, which encodes the gamma2 subunit of AMPK, an enzyme central to cellular energy homeostasis [3].
  • The cardiac phenotype observed in humans harbouring genetic mutations in the gamma 2 regulatory subunit (PRKAG2) of AMPK is consistent with abnormal glycogen accumulation in the heart [7].
  • The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size [9].
  • The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database [9].

Anatomical context of PRKAG2

  • As deleterious alleles were not found in other AMPK subunit isoforms, the mutations affecting PRKAG2 are likely to confer a specific alteration of AMPK function of particular importance in the myocardium [3].
  • The authors describe a 38-year-old man with a new heterozygous PRKAG2 mutation (Ser548Pro) manifesting by hypertrophic cardiomyopathy, severe conduction system abnormalities, and skeletal muscle glycogenosis [10].
  • Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2 [11].

Associations of PRKAG2 with chemical compounds

  • Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5'-AMP-activated protein kinase, to human chromosome 7q36 [8].
  • BACKGROUND: Some PRKAG2 mutations in the human gene encoding for the gamma-subunit of the adenosine monophosphate-activated protein kinase (AMPK) recently have been shown to cause rhythm disturbances (often fatal) in affected patients [12].

Other interactions of PRKAG2

  • PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing [9].
  • Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2 [13].
  • BACKGROUND: Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown [14].

Analytical, diagnostic and therapeutic context of PRKAG2


  1. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Arad, M., Benson, D.W., Perez-Atayde, A.R., McKenna, W.J., Sparks, E.A., Kanter, R.J., McGarry, K., Seidman, J.G., Seidman, C.E. J. Clin. Invest. (2002) [Pubmed]
  2. Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. Murphy, R.T., Mogensen, J., McGarry, K., Bahl, A., Evans, A., Osman, E., Syrris, P., Gorman, G., Farrell, M., Holton, J.L., Hanna, M.G., Hughes, S., Elliott, P.M., Macrae, C.A., McKenna, W.J. J. Am. Coll. Cardiol. (2005) [Pubmed]
  3. Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. Oliveira, S.M., Ehtisham, J., Redwood, C.S., Ostman-Smith, I., Blair, E.M., Watkins, H. J. Mol. Cell. Cardiol. (2003) [Pubmed]
  4. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. Gollob, M.H., Green, M.S., Tang, A.S., Gollob, T., Karibe, A., Ali Hassan , A.S., Ahmad, F., Lozado, R., Shah, G., Fananapazir, L., Bachinski, L.L., Roberts, R., Hassan, A.S. N. Engl. J. Med. (2001) [Pubmed]
  5. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Burwinkel, B., Scott, J.W., Bührer, C., van Landeghem, F.K., Cox, G.F., Wilson, C.J., Grahame Hardie, D., Kilimann, M.W. Am. J. Hum. Genet. (2005) [Pubmed]
  6. Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson-White syndrome. Patel, V.V., Arad, M., Moskowitz, I.P., Maguire, C.T., Branco, D., Seidman, J.G., Seidman, C.E., Berul, C.I. J. Am. Coll. Cardiol. (2003) [Pubmed]
  7. Glycogen storage disease as a unifying mechanism of disease in the PRKAG2 cardiac syndrome. Gollob, M.H. Biochem. Soc. Trans. (2003) [Pubmed]
  8. Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5'-AMP-activated protein kinase, to human chromosome 7q36. Lang, T., Yu, L., Tu, Q., Jiang, J., Chen, Z., Xin, Y., Liu, G., Zhao, S. Genomics (2000) [Pubmed]
  9. Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Gollob, M.H., Seger, J.J., Gollob, T.N., Tapscott, T., Gonzales, O., Bachinski, L., Roberts, R. Circulation (2001) [Pubmed]
  10. A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Laforêt, P., Richard, P., Said, M.A., Romero, N.B., Lacene, E., Leroy, J.P., Baussan, C., Hogrel, J.Y., Lavergne, T., Wahbi, K., Hainque, B., Duboc, D. Neuromuscul. Disord. (2006) [Pubmed]
  11. Gene mutations in apical hypertrophic cardiomyopathy. Arad, M., Penas-Lado, M., Monserrat, L., Maron, B.J., Sherrid, M., Ho, C.Y., Barr, S., Karim, A., Olson, T.M., Kamisago, M., Seidman, J.G., Seidman, C.E. Circulation (2005) [Pubmed]
  12. Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Light, P.E., Wallace, C.H., Dyck, J.R. Circulation (2003) [Pubmed]
  13. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. Arad, M., Maron, B.J., Gorham, J.M., Johnson, W.H., Saul, J.P., Perez-Atayde, A.R., Spirito, P., Wright, G.B., Kanter, R.J., Seidman, C.E., Seidman, J.G. N. Engl. J. Med. (2005) [Pubmed]
  14. Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. Morita, H., Larson, M.G., Barr, S.C., Vasan, R.S., O'Donnell, C.J., Hirschhorn, J.N., Levy, D., Corey, D., Seidman, C.E., Seidman, J.G., Benjamin, E.J. Circulation (2006) [Pubmed]
  15. Molecular genetic analysis of PRKAG2 in sporadic Wolff-Parkinson-White syndrome. Vaughan, C.J., Hom, Y., Okin, D.A., McDermott, D.A., Lerman, B.B., Basson, C.T. J. Cardiovasc. Electrophysiol. (2003) [Pubmed]
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