Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome

	Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome
	Guo, FF; Sun, YX; Wang, XC; Wang, H; Wang, J; Gong, TY; Chen, XZ; Zhang, P; Su, L; Fu, GS; Su, J; Yang, SL; Lai, R; Jiang, CY; Liang, P
	2019
发表期刊	CIRCULATION RESEARCH
ISSN	0009-7330
卷号	124 期号:1 页码:66-78
摘要	Rationale: Short QT syndrome (SQT) is a rare but arrhythmogenic disorder featured by shortened ventricular repolarization and a propensity toward life-threatening ventricular arrhythmias and sudden cardiac death. Objective: This study aimed to investigate the single-cell mechanism of SQT using patient-specific and genecorrected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods and Results: One SQT patient carrying missense mutation T618I in potassium voltage-gated channel subfamily H member 2 (KCNH2) was recruited as well as 2 healthy control subjects in this study. Control and SQT patient-specific iPSCs were generated from skin fibroblasts using nonintegrated Sendai virus. The KCNH2 T618I mutation was corrected by genome editing in SQT iPSC lines to generate isogenic controls. All iPSCs were differentiated into iPSC-CMs using monolayer-based differentiation protocol. SQT iPSC-CMs exhibited abnormal action potential phenotype featured by shortened action potential duration and increased beat-beat interval variability, when compared with control and gene-corrected iPSC-CMs. Furthermore, SQT iPSC-CMs showed KCNH2 gain-of-function with increased rapid delayed rectifying potassium current (I Kr) density and enhanced membrane expression. Gene expression profiling of iPSC-CMs exhibited a differential cardiac ionchannel gene expression profile of SQT. Moreover, QTc of SQT patient and action potential durations of SQT iPSC-CMs were both normalized by quinidine, indicating that quinidine is beneficial to KCNH2 T618I of SQT. Importantly, shortened action potential duration phenotype observed in SQT iPSC-CMs was effectively rescued by a short-peptide scorpion toxin BmKKx2 with a mechanism of targeting KCNH2. Conclusions: We demonstrate that patient-specific and gene-corrected iPSC-CMs are able to recapitulate singlecell phenotype of SQT, which is caused by the gain-of-function mutation KCNH2 T618I. These findings will help elucidate the mechanisms underlying SQT and discover therapeutic drugs for treating the disease by using peptide toxins as lead compounds. (Circ Res. 2019; 124: 66-78. DOI: 10.1161/ CIRCRESAHA. 118.313518.)
收录类别	SCIE
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/12449
专题	科研部门_天然药物功能蛋白质学科组（赖仞）
推荐引用方式 GB/T 7714	Guo, FF,Sun, YX,Wang, XC,et al. Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome[J]. CIRCULATION RESEARCH,2019,124(1):66-78.
APA	Guo, FF.,Sun, YX.,Wang, XC.,Wang, H.,Wang, J.,...&Liang, P.(2019).Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome.CIRCULATION RESEARCH,124(1),66-78.
MLA	Guo, FF,et al."Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome".CIRCULATION RESEARCH 124.1(2019):66-78.

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