AMPK Methods and Protocols

Chapter 37

Humanγ2-AMPK Mutations

Arash Yavari, Dhruv Sarma, and Eduardo B. Sternick

Abstract

In humans, dominant mutations in the gene encoding the regulatoryγ2-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 high-
lighting 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 inPRKAG2,
together with less commonly described extracardiac features, its prognosis, and principles of management.

Key wordsAMPK, Cardiac conduction disease, Cardiac hypertrophy, Cardiomyopathy, Glycogen

storage, LVH, Pre-excitation,PRKAG2, Wolff-Parkinson-White syndrome

1 Discovery of Mutations inPRKAG2as a Cause of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the commonest inherited

cardiac disease (with a prevalence of ~1 in 500 individuals) segre-

gating as an autosomal dominant trait. HCM is defined clinically by

the presence of left ventricular hypertrophy (LVH, i.e., increased

thickening of the left ventricular wall) which is not solely explained

by abnormal cardiac loading conditions [1, 2]. While the majority

of HCM cases are recognized to be asymptomatic, its most dra-

matic clinical complication—and one which has gained widespread

public recognition in the context of competitive athletes—is sud-

den cardiac death (SCD) [3]. Pathologically, HCM is characterized

by ventricular hypertrophy (often primarily affecting the interven-

tricular septum), cardiomyocyte disarray, and cardiac fibrosis. While

the genetics of HCM are complex, with significant genetic and

allelic heterogeneity, the majority of the ~500 causal mutations

described reside in components of the sarcomere—the fundamental

Dietbert Neumann and Benoit Viollet (eds.),AMPK: Methods and Protocols, Methods in Molecular Biology, vol. 1732,
https://doi.org/10.1007/978-1-4939-7598-3_37,©Springer Science+Business Media, LLC 2018

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