title: Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sparks
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Kanter
authors.forename: Kate
authors.initials: K
authors.lastname: McGarry
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D001483:Base Sequence; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D002352:Carrier Proteins; D004247:DNA / Q000235:genetics; D005260:Female; D005800:Genes, Fungal; D006008:Glycogen Storage Disease / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics; D014170:Transformation, Genetic; D014927:Wolff-Parkinson-White Syndrome / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D009097:Multienzyme Complexes; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004247:DNA; D011494:Protein Kinases; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases; C078651:SNF4 protein, S cerevisiae; D055372:AMP-Activated Protein Kinases