van den Brink Lettine, Brandão Karina O, Yiangou Loukia, Blanch-Asensio Albert, Mol Mervyn P H, Mummery Christine L, Verkerk Arie O, Davis Richard P
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
Department of Applied Stem Cell Technologies, University of Twente, Enschede, Netherlands.
Front Physiol. 2021 Dec 16;12:755642. doi: 10.3389/fphys.2021.755642. eCollection 2021.
While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in - or -orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2) or tail region (KCNH2) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele () as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their -oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing mutations depending on whether it is present in or . This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.
虽然离子通道基因中的罕见突变是遗传性心律失常的主要原因，但常见的基因变异也是导致突变携带者临床异质性的重要因素。常见的单核苷酸多态性（SNP）KCNH2-K897T与QT间期持续时间有关，但其对2型长QT综合征（LQT2）患者疾病表型的影响仍不清楚。人类诱导多能干细胞（hiPSC）与基因编辑技术的进步相结合，已被证明是一种用于模拟心脏遗传疾病和识别导致疾病表达变异的变异体的宝贵工具。在本研究中，我们使用了同基因的hiPSC来源的心肌细胞（hiPSC-CM），以确定在钾离子通道人醚-去极化相关基因（hERG）的孔环结构域（KCNH2）或尾部区域（KCNH2）中，KCNH2-K897T SNP与导致LQT2的错义变异处于同向或反向时的功能后果。当KCNH2-K897T与主要突变位于同一等位基因（同向）时，hiPSC-CM中的hERG通道与反向的对应通道相比，表现出更快的激活和失活动力学。与此一致的是，KCNH2-K897T处于同向的hiPSC-CM具有更长的动作电位和场电位持续时间。此外，在对hERG进行药理学阻断后，心律失常事件的发生率增加。总体而言，这些结果表明，常见的多态性KCNH2-K897T对导致LQT2的突变的影响因其是同向还是反向而异。本研究证实了hiPSC-CM是一个强大的平台，可用于研究常见基因变异对遗传性心律失常的修饰作用，并有助于阐明它们对这些疾病可变表达的贡献。
