Popeye Domain Containing Protein 2 (POPDC2) and inherited forms of AV block: Mechanistic investigations on the modulation of cardiac ion channels by POPDC2

编码离子通道或其辅助亚基的基因突变是遗传性心律失常的主要原因。尽管在理解室性心律失常的遗传起源方面取得了很大进展，但冲动产生或传导受损的疾病的遗传起源大多仍然难以捉摸。在这种情况下，鉴定含有大力水手结构域的蛋白质（POPDC）作为离子通道调节剂是高度相关的，特别是POPDC 2敲除小鼠显示出应激诱导的窦房心动过缓。在对POPDC2基因敲除小鼠表型的研究进展中，我们能够在我的实验室中证明POPDCs以cAMP依赖性方式调节双孔结构域钾通道TREK-1。目前尚不清楚POPDC蛋白是否也调节其他心脏离子通道，这是我们在此提出的本项目中想要解决的主要问题之一。在我们对肌营养不良和房室传导阻滞患者中首次报告的POPDC1突变的致病机制进行功能研究后，我们在患有三度房室传导阻滞的双胞胎中使用了全外显子组测序方法，并确定了POPDC2中的杂合突变是最有可能致病的遗传缺陷。拟议项目的目的是功能性地描述这种POPDC2W188 * 突变，并确定致病机制。此外，我们的目标是在这个项目中确定POPDC蛋白的TREK-1调制的分子机制。然而，拟议项目的一个基本任务是鉴定POPDC2W188 * 突变的致病机制，我们计划通过例如转基因POPDC2W188 * 小鼠的功能分析来实现。我们的研究应该提供一个重要的贡献，对TREK-1和其他心脏离子通道的分子调节的理解，从而提供功能证据POPDC2W188 * 基因缺陷是如何导致遗传性传导障碍。

Mutations in genes encoding ion channels or their accessory subunits are the primary cause of inherited forms of cardiac arrhythmias. Despite great progress in the understanding of the genetic origins of ventricular arrhythmias, the genetic origins of diseases with impaired impulse generation or conduction mostly remain elusive. In this context, the identification of Popeye Domain Containing Proteins (POPDC) as ion channel modulators was highly relevant, in particular as POPDC2 knock-out mice showed a stress-induced sino-atrial bradycardia. In the progress of this study on the phenotype of the POPDC2 knock-out mice, we were able to show in my laboratory that POPDCs modulate the two-pore-domain potassium channel TREK-1 in a cAMP-dependent manner. Currently it remains unclear whether POPDC proteins also modulate other cardiac ion channels, which is one of the major questions we would like to address within this project proposed here. After we contributed functional investigations on the disease-causing mechanism of the first reported POPDC1 mutations in patients which suffer from muscular dystrophy und AV blockades, we have utilized a whole exome sequencing approach in twins with a third degree AV block and identified a heterozygous mutation in POPDC2 as the most likely disease-causing genetic defect. The aim of the proposed project is to functionally characterize this POPDC2W188* mutation and to identify the disease-causing mechanism. Moreover, we aim to identify within this project the molecular mechanisms of the TREK-1 modulation by POPDC proteins. An essential task of the proposed project is however the identification of the disease-causing mechanism of the POPDC2W188* mutation which we plan to achieve by the functional analyses of transgenic POPDC2W188* mice for instance. Our investigations should provide an essential contribution towards the understanding of the molecular modulation of TREK-1 and other cardiac ion channels and thus provide the functional evidence how the POPDC2W188* gene defect is leading to inherited conduction disorders.