PRKAG2心脏综合征是以心脏肥大为特征的人类心肌病的一种独特形式，心室预激和进行性心脏传导障碍。然而,目前尚不清楚PRKAG2基因突变是如何导致这种复杂疾病的.为了研究潜在的分子机制，我们从两个在PRKAG2基因中携带杂合错义突变c.905G>A(R302Q)的兄弟中产生了疾病特异性hiPSC来源的心肌细胞,并通过CRISPR-Cas9介导的基因组编辑进一步校正了R302Q突变.疾病特异性hiPSC心肌细胞概括了PRKAG2心脏综合征的许多表型，包括细胞扩大，电生理不规则和糖原储存。此外,我们发现PRKAG2-R302Q突变导致AMPK活性增加，导致广泛的糖原沉积和心肌细胞肥大。最后，我们证实了由特定的PRKAG2-R302Q突变引起的PRKAG2心脏综合征表型的破坏可以通过小分子抑制AMPK活性来缓解，并可以通过CRISPR-Cas9介导的基因组校正来挽救。我们的结果表明，疾病特异性hiPSC-CM和基因校正的hiPSC-心肌细胞将是一个非常有用的平台，并测试基于自体细胞的疗法，PRKAG2心脏综合征。
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.
