期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 117, 期 -, 页码 49-61出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.02.007
关键词
PRKAG2 cardiac syndrome; Human induced pluripotent stem cells; Cardiomyocytes; Cardiac hypertrophy; Glycogen storage; AMPK activity
资金
- National Natural Science Foundation of China (NSFC) [31571527, 81322003]
- Science and Technology Commission of Shanghai Municipality [17XD1400300]
- National Key R&D Program of China [2016YFC1000500, 2016YFC1305100]
- National Key Scientific Research Projects [2014CBA02003]
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.
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