title: Identification of a novel de novo mutation associated with PRKAG2 cardiac syndrome and early onset of heart failure.
abstract: BACKGROUND
  The major structure elements of the AMP-activated protein kinase (AMPK) are α, β, and γ sunbunits. Mutations in γ2 subunit (PRKAG2) have been associated with a cardiac syndrome including inherited ventricular preexcitation, conduction disorder and hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the present study was to identify PRKAG2 syndrome among patients presenting with left ventricular hypertrophy (LVH).
  
  
  RESULTS
  Nineteen unrelated subjects with unexplained LVH were clinically and genetically evaluated. Among 4 patients with bradycardia, manifestations of preexcitation were only found in a 19 year old male who also developed congestive heart failure 3 years later. Electrophysiological study of this case identified the coexistence of an AV accessory pathway and AV conduction defect. Histological analysis of his ventricular tissue isolated by biopsy confirmed excessive glycogen accumulation, prominent myofibrillar disarray and interstitial fibrosis. Direct sequencing of his DNA revealed a heterozygous mutation in PRKAG2 consisting of an A-to-G transition at nucleotide 1453 (c.1453A>G), predicting a substitution of a glutamic acid for lysine at highly-conserved residue 485 (p.Lys485Glu, K485E), which was absent in his unaffected family members and in 215 healthy controls. To assess the role of K485 in the structure and function of the protein, computational modeling calculations and conservation analyses were performed. Electrostatic calculations indicate that K485 forms a salt bridge with the conserved D248 residue in the AMPK β subunit, which is critical for proper regulation of the enzyme, and the K485E mutant disrupts the connection.
  
  
  CONCLUSIONS
  Our study identifies a novel de novo PRKAG2 mutation in a young, in which progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2 gene in patients with unexplained LVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure.
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Bai
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Cuntai
authors.initials: C
authors.lastname: Zhang
authors.forename: Ruifu
authors.initials: R
authors.lastname: Zhao
authors.forename: Deli
authors.initials: D
authors.lastname: Wan
authors.forename: Xinshan
authors.initials: X
authors.lastname: Chen
authors.forename: Gabriel
authors.initials: G
authors.lastname: Caceres
authors.forename: Daniel
authors.initials: D
authors.lastname: Barr
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D005260:Female; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases