Author + information
- Dan Hu,
- Daniel Barr,
- Heather McManus,
- Norma Balderrabano-Saucedo,
- Ryan Pfeiffer,
- Hector Barajas and
- Dong Hu
Introduction: Human mutations in PRKAG2, the gene encoding the γ2 subunit of AMP activated protein kinase (AMPK), lead to diverse cardiac phenotypes with variable clinical expressivity, named as PRKAG2 syndrome. Thus far, 15 causative mutations have been identified in the gene. Here we report novel mutations in 2 PRKAG2 syndrome families with featured phenotypes.
Methods: Subjects were evaluated by detailed medical history, family history, and clinical examination. Next generation sequencing of targeted genes for sudden cardiac death was performed. To assess the role of mutations in the structure and function of the protein, computational modeling calculations and conservation analyses were performed.
Results: Proband 1 was a 45 y/o asymptomatic male with non-obstructive asymmetric septal HCM and hypertension. Holter showed 2nd degree AVB (type 2) with minimum heart rate 25 bpm. Proband 2 began to present palpitation and syncope at 14 y/o with non-obstructive septal HCM (33 mm). Holter displayed sinus bradycardia with pauses up to 2.9 s, and frequent PVCs and self-limited VT. Genetic sequencing revealed heterozygous PRKAG2-L341S and PRKAG2-H401D mutations in proband 1 and 2 respectively. Proband 1’s mother and maternal uncle also presented as HCM and carried the same mutation. His uncle underwent heart transplantation. Proband 2’s maternal grandfather and 2 brothers died suddenly at age of 42, 17, and 36 y/o. His mother, implanted pacemaker for syncope 14 years ago, refused genetic testing. Computational modelling demonstrated that K485E disrupted a salt bridge connecting the β and γ subunits of AMPK, R302Q decreased the binding affinity of the kinase for ATP, and both N488I and L341S lead to structural instability in the Bateman domain which disrupts the intramolecular regulation of the kinase. The H401D mutation generated salt bridge contacting with all of the nearby histidine and arginine residues, which will lead to a change in the nucleotide binding affinity.
Conclusions: Our study identifies novel PRKAG2 mutations in 2 males and their family members. The pathogenic mechanisms of different mutations are various from each other, which will lead to different clinical phenotype and severity.
Poster Hall, Hall C
Sunday, March 19, 2017, 9:45 a.m.-10:30 a.m.
Session Title: The Evolving World of LVADs, Transplant and Other Novel Discoveries
Abstract Category: 13. Heart Failure and Cardiomyopathies: Clinical
Presentation Number: 1294-260
- 2017 American College of Cardiology Foundation