A novel, de novo mutation in PRKAG2 gene: infantile-onset phenotype and signaling pathway involved

Yanchun Xu, Alex Gray, D. Grahame Hardie, Alper Uzun, Sunil Shaw, James Padbury, Chanika Phornphutkul, Yi-Tang Tseng (Lead / Corresponding author)

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PRKAG2 encodes the γ2-subunit isoform of the 5' AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved and therapeutic options for K475E mutation using cells stably expressing human wild type (WT) or the K475E mutant. In HEK293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced response to phenformin and increases in phosphorylation of P70S6K and 4E-BP1. Primary fibroblasts from the patient with the K475E mutation also showed marked increases in phosphorylation of P70S6K and 4E-BP1, compared to those from age-matched, non-diseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset PRKAG2 mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin (mTOR) signaling pathway, which can be reversed with rapamycin..

Original languageEnglish
Pages (from-to)H283-H292
Number of pages10
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology (AJP - Heart and Circulatory Physiology)
Issue number2
Early online date26 May 2017
Publication statusPublished - 1 Aug 2017


  • Ampk
  • Cardiac hypertrophy
  • PRKAG2 gene mutation
  • Rapamycin
  • H9c2 cells


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