Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002 Feb;109(3):357-62
Date
02/06/2002Pubmed ID
11827995Pubmed Central ID
PMC150860DOI
10.1172/JCI14571Scopus ID
2-s2.0-0036167225 (requires institutional sign-in at Scopus site) 488 CitationsAbstract
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. 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.
Author List
Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CEMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAmino Acid Sequence
Base Sequence
Cardiomyopathy, Hypertrophic, Familial
Carrier Proteins
DNA
Female
Genes, Fungal
Glycogen Storage Disease
Humans
Male
Molecular Sequence Data
Multienzyme Complexes
Mutation
Mutation, Missense
Pedigree
Protein Kinases
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Sequence Homology, Amino Acid
Transcription Factors
Transformation, Genetic
Wolff-Parkinson-White Syndrome
