Pathogenesis of hERG Mutations in Human Long QT Syndrome

 描述(申请人提供)：长QT综合征是一种以心脏复极延迟和心律失常和猝死风险增加为特征的疾病。先天性和后天(如药物诱发)的QT间期延长综合征都已被发现。长QT综合征2型(LQT2)是由KCNH2基因(也称为hERG1或HERG)突变引起的。KCNH2编码Kv11.1钾通道，该通道在心脏传导快速激活的延迟整流钾电流(Ikr)。Kv11.1通道在先天性和药物诱导的长QT综合征中起重要作用。LQT2是第二种最常见的先天性长QT综合征，占长QT综合征基因分型病例的35%至40%。许多药物通过抑制Kv11.1通道功能而导致药物性长QT综合征。Kv11.1通道功能障碍导致动作电位复极延迟，导致QT延长和心律失常。在之前的资助阶段，我们已经确定了异构体转换是LQT2中Kv11.1通道功能障碍的一种新机制。我们还证明了Kv11.1 C末端亚型的相对表达在Kv11.1通道功能的调节中起着重要作用，并发展了一种反义方法来增加功能性Kv11.1亚型的表达。在本应用中，我们将研究Kv11.1亚型表达在发育和组织特异性调控下的机制，并证明Kv11.1亚型表达的调节是药物诱导抑制Kv11.1通道功能的新机制。此外，我们将在诱导的多能干细胞来源的心肌细胞和敲入小鼠模型中测试反义诱导的Kv11.1通道功能上调。该应用的具体目的是：目的1)研究Kv11.1亚型表达的组织特异性和发育调控机制。目的2)明确Kv11.1亚型相对表达的调节是药物抑制Kv11.1通道功能的一种新机制。目的3)研究反义基因对携带不同KCNH2突变的LQT2患者特异性诱导的多能干细胞来源的心肌细胞中功能性Kv11.1亚型表达的上调作用。目的4)研究反义核酸对敲入小鼠功能性Kv11.1亚型表达的上调作用。本研究所获得的知识将加强我们对长QT综合征分子机制的理解，并为开发长QT综合征的新的治疗策略提供信息。

 DESCRIPTION (provided by applicant): Long QT syndrome is a disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmias and sudden death. Both congenital and acquired (such as drug-induced) forms of long QT syndrome have been identified. Long QT syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene (also known as hERG1 or hERG). KCNH2 encodes the Kv11.1 K+ channel that conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. The Kv11.1 channel plays an important role in congenital and drug-induced forms of long QT syndrome. LQT2 is the second most prevalent form of congenital long QT syndrome accounting for 35 to 40% of genotyped cases of long QT syndrome. Many drugs cause drug- induced long QT syndrome by inhibition of Kv11.1 channel function. Kv11.1 channel dysfunction results in the delay in action potential repolarization, leading to QT prolongation and cardiac arrhythmias. In the previous funding period, we have identified isoform switch as a novel mechanism of Kv11.1 channel dysfunction in LQT2. We also showed that the relative expression of Kv11.1 C-terminal isoforms plays an important role in the regulation of Kv11.1 channel function, and developed an antisense approach to increase the functional Kv11.1 isoform expression. In the present application, we will study the mechanisms underling the developmental and tissue-specific regulation of Kv11.1 isoform expression and demonstrate the modulation of Kv11.1 isoform expression as a novel mechanism of drug-induced suppression of Kv11.1 channel function. In addition, we will test the antisense-induced upregulation of Kv11.1 channel function in induced pluripotent stem cell-derived cardiomyocytes and a knock-in mouse model. The specific aims of this application are: Aim 1) To study the mechanisms underlying the tissue-specific and developmental regulation of Kv11.1 isoform expression. Aim 2) To identify the modulation of the relative expression Kv11.1 isoforms as a novel mechanism of drug-induced suppression of Kv11.1 channel function. Aim 3) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in LQT2 patient-specific induced pluripotent stem cell-derived cardiomyocytes that carry different KCNH2 mutations. Aim 4) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in a knock-in mouse model. The knowledge gained from this study will strengthen our understanding of the molecular mechanisms of long QT syndrome and provide information directed towards the development of novel therapeutic strategies for long QT syndrome.