Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells. (April 2018)

• Record Type: Journal Article
• Authors: Zhan, Yongkun; Sun, Xiaolei; Li, Bin; Cai, Huanhuan; Xu, Chen; Liang, Qianqian; Lu, Chao; Qian, Ruizhe; Chen, Sifeng; Yin, Lianhua; Sheng, Wei; Huang, Guoying; Sun, Aijun; Ge, Junbo; Sun, Ning
• Is Part Of: Journal of molecular and cellular cardiology. Volume 117(2018)
• Page Start: 49
• Page End: 61
• Publication Date: 2018-04
• Subjects: PRKAG2 cardiac syndrome -- Human induced pluripotent stem cells -- Cardiomyocytes -- Cardiac hypertrophy -- Glycogen storage -- AMPK activity; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.02.007
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.905G>A (R302Q) in the PRKAG2 gene and further corrected the R302Q mutation with CRISPR-Cas9 mediated genome editing. Disease-specific hiPSC-cardiomyocytes recapitulated many phenotypes of PRKAG2 cardiac syndrome including cellular enlargement, electrophysiological irregularities and glycogen storage. In addition, we found that the PRKAG2-R302Q mutation led to increased AMPK activities, resulting in extensive glycogen deposition and cardiomyocyte hypertrophy. Finally we confirmed that disrupted phenotypes of PRKAG2 cardiac syndrome caused by the specific PRKAG2-R302Q mutation can be alleviated by small molecules inhibiting AMPK activity and be rescued with CRISPR-Cas9 mediated genome correction. Our results showed that disease-specific hiPSC-CMs and genetically-corrected hiPSC-cardiomyocytes would be a very useful platform for understanding the pathogenesis of, and testing autologous cell-based therapies for, PRKAG2 cardiac syndrome. Abstract : Graphical abstractUnlabelled Image Highlights: Patient-specific hiPSC-CM model of PRKAG2 cardiac syndrome is successfully generated. Patient-specific hiPSC-CMs recapitulate critical properties of the PRKAG2 cardiac syndrome in vitro . PRKAG2-R302Q mutation increases AMPK activity, leading to extensive glycogen deposition in hiPSC-CMs. Patient-specific hiPSC-CMs provide a new way to study the pathogenesis of PRKAG2 cardiac syndrome. CRISPR-Cas9 mediated genome correction can rescue the phenotypes of PRKAG2 cardiac syndrome.