Robertson G A, January C T
Dept. of Physiology, University of Wisconsin-Madison, 601 Science Drive, Madison, WI 53711, USA.
Handb Exp Pharmacol. 2006(171):349-55. doi: 10.1007/3-540-29715-4_14.
The human ether-a-go-go-related gene (hERG) encodes an ion channel subunit underlying IKr, a potassium current required for the normal repolarization of ventricular cells in the human heart. Mutations in hERG cause long QT syndrome (LQTS) by disrupting IKr, increasing cardiac excitability and, in some cases, triggering catastrophic torsades de pointes arrhythmias and sudden death. More than 200 putative disease-causing mutations in hERG have been identified in affected families to date, but the mechanisms by which these mutations cause disease are not well understood. Of the mutations studied, most disrupt protein maturation and reduce the numbers of hERG channels at the membrane. Some trafficking-defective mutants can be rescued by pharmacological agents or temperature. Here we review evidence for rescue of mutant hERG subunits expressed in heterologous systems and discuss the potential for therapeutic approaches to correcting IKr defects associated with LQTS.
人类醚 - 去极化相关基因（hERG）编码一种离子通道亚基，该亚基是IKr电流的基础，IKr电流是人类心脏心室细胞正常复极化所必需的钾电流。hERG突变通过破坏IKr电流、增加心脏兴奋性，在某些情况下引发灾难性的尖端扭转型室性心律失常和猝死，从而导致长QT综合征（LQTS）。迄今为止，在受影响的家族中已鉴定出200多个hERG中假定的致病突变，但这些突变导致疾病的机制尚未完全了解。在所研究的突变中，大多数会破坏蛋白质成熟并减少膜上hERG通道的数量。一些运输缺陷型突变体可以通过药物或温度挽救。在这里，我们综述了在异源系统中表达的突变hERG亚基挽救的证据，并讨论了纠正与LQTS相关的IKr缺陷的治疗方法的潜力。
