Identification of a Novel De Novo Mutation Associated with PRKAG2 Cardiac Syndrome and Early Onset of Heart Failure

Introduction: The major structure elements of the AMP-activated protein kinase (AMPK) are alpha, beta, and gamma sunbunits. Mutations in gamma 2 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). Methods and 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 b 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.