title: Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency.
abstract: Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified. Analyzing four sporadic, unrelated patients, we found no mutations either in the eight genes encoding phosphorylase kinase subunits or in the two genes encoding the muscle and brain isoforms of glycogen phosphorylase. However, in three of five patients, we identified identical heterozygous R531Q missense mutations of the PRKAG2 gene, which encodes the gamma 2-subunit of AMP-activated protein kinase, a key regulator of energy balance. Biochemical characterization of the recombinant R531Q mutant protein showed >100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha -subunit. Other PRKAG2 missense mutations were previously identified in patients with autosomal dominant hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, characterized by juvenile-to-adult clinical onset, moderate cardiac glycogenosis, disturbed excitation conduction, risk of sudden cardiac death in midlife, and molecular perturbations that are similar to--but less severe than--those observed for the R531Q mutation. Thus, recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome. R531Q and other PRKAG2 mutations enhance the basal activity and alpha -subunit phosphorylation of AMP-activated protein kinase, explaining the dominant nature of PRKAG2 disease mutations. Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous. However, the existence of a heart-specific primary phosphorylase kinase deficiency is questionable, because no phosphorylase kinase mutations were found.
authors.affiliation: Institut fur Physiologische Chemie, Medizinische Fakultat, Ruhr-Universitat Bochum, Bochum, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.forename: Frank K H
authors.initials: FK
authors.lastname: van Landeghem
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Grahame Hardie
authors.forename: Manfred W
authors.initials: MW
authors.lastname: Kilimann
mesh_terms: D055372:AMP-Activated Protein Kinases; D000483:Alleles; D000595:Amino Acid Sequence; D006332:Cardiomegaly / Q000000981:diagnostic imaging; D009202:Cardiomyopathies / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D003062:Codon; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D005787:Gene Frequency; D005982:Glutathione Transferase / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D010764:Phosphorylase Kinase / Q000172:deficiency*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D003062:Codon; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D010764:Phosphorylase Kinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases