Department of Experimental Cardiology, Masonic Medical Research Institute, Utica, NY 13501, USA.
Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
Int J Mol Sci. 2021 Jul 1;22(13):7108. doi: 10.3390/ijms22137108.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a "pseudo" QRS complex suggesting reduced inward current(s). Voltage clamp analysis of I showed no difference in the magnitude of current. Measurements of I reveal a 60% reduction in I density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of I was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of I due to a mutation in coupled with and a gain of function in I due to a mutation in .
人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）用于心脏疾病的遗传模型。我们报告了一种心律失常综合征，包括早期复极综合征（ERS）和短 QT 综合征（SQTS）。索引患者（MMRL1215）在电击后发生心律失常性晕厥，并发现携带六种突变。在患者来源的 hiPSC-CMs 中检查了这些突变导致的功能改变。在 MMRL1215 和健康对照的 hiPSC-CMs 中进行了电生理记录。指数患者的心电图分析显示 QRS 复合体模糊和 QTc = 326 ms。来自 MMRL1215 心肌细胞的动作电位（AP）记录显示自发活动较慢，AP 持续时间较短。来自 MMRL1215 hiPSC-CMs 的场电位记录缺乏“伪”QRS 复合体，表明内向电流减少。I 的电压钳分析表明电流幅度没有差异。I 的测量表明 MMRL1215 hiPSC-CMs 中的 I 密度降低了 60%。I 的稳定失活和恢复不受影响。mRNA 分析显示，ANK2 和 SCN5A 在 MMRL1215 来源的 hiPSC-CM 中显著减少，与电生理记录一致。ERS/SQTS 表型的多基因原因可能是由于突变导致的耦合 I 的丧失，以及突变导致的 I 的功能获得。
