Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2^W188⁎), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K_2P) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2^W188⁎ causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2^W188⁎ knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2^W188⁎ loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.

尽管最近在了解心脏离子通道功能及其在遗传性室性心律失常中的作用方面取得了进展，但心脏传导障碍的分子基础往往仍未解决。我们旨在使用全外显子组测序 (WES) 方法阐明家族性房室传导阻滞 (AVB) 的遗传背景。在具有三级 AVB 的单卵双胞胎和另一个具有一级 AVB 的无关家庭中，我们在POPDC2基因中发现了一个杂合的无义突变，导致在 188 位（POPDC2 ^W188⁎)，删除部分 cAMP 绑定域。含有 Popeye 结构域 (POPDC) 的蛋白质主要在骨骼肌和心脏中表达，尤其是在小鼠的窦房结中 POPDC2 的高表达。我们现在通过定量 PCR 实验表明，在人心脏中，POPDC 调节的双孔域钾 (K _2P ) 通道 TREK-1 优先在房室结中表达。非洲爪蟾卵母细胞的共表达研究表明 POPDC2 ^W188⁎导致功能丧失，TREK-1 调节受损。与小鼠窦房结中 POPDC2 的高表达水平一致，POPDC2 ^W188⁎敲入小鼠表现出压力诱导的窦性心动过缓和停顿，之前也报道了POPDC2和TREK-1敲除小鼠的表型。我们提出 POPDC2 ^W188⁎功能丧失突变通过 TREK-1 的异常调节导致 AVB 发病机制，强调POPDC2代表了一种用于心脏传导障碍的新型心律失常基因。