Back to Search
Start Over
Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells.
- Source :
-
Journal of Molecular & Cellular Cardiology . Apr2018, Vol. 117, p49-61. 13p. - Publication Year :
- 2018
-
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 FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222828
- Volume :
- 117
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular & Cellular Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 128542431
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2018.02.007