Human γ2-AMPK Mutations.

Abstract

In humans, dominant mutations in the gene encoding the regulatory γ2-subunit of AMP-activated protein kinase (PRKAG2) result in a highly penetrant phenotype dominated by cardiac features: left ventricular hypertrophy, ventricular pre-excitation, atrial tachyarrhythmia, cardiac conduction disease, and myocardial glycogen storage. The discovery of a link between the cell's fundamental energy sensor, AMPK, and inherited cardiac disease catalyzed intense interest into the biological role of AMPK in the heart. In this chapter, we provide an introduction to the spectrum of human disease resulting from pathogenic variants in PRKAG2, outlining its discovery, clinical genetics, and current perspectives on its pathogenesis and highlighting mechanistic insights derived through the evaluation of disease models. We also present a clinical perspective on the major components of the cardiomyopathy associated with mutations in PRKAG2, together with less commonly described extracardiac features, its prognosis, and principles of management.