The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency.
The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency.
复制标题
hERG 钾通道 PAS 结构域中的突变 L69P 通过运输缺陷导致 LQTS。
DOI：
10.1080/19336950.2020.1751522
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kauferstein,Silke
中科院分区：
文献类型：
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作者：
Jenewein,Tina;Kanner,ScottA;Bauer,Daniel;Hertel,Brigitte;Colecraft,HenryM;Moroni,Anna;Thiel,Gerhard;Kauferstein,Silke
先天性长QT综合征（LQTS）是一种心脏疾病，其特征是心电图上QT间期延长，对室性心律失常和心源性猝死的易感性增加。LQTS的常见原因是KCNH 2基因（也称为人类ether-a-go-go-related基因或hERG）的突变，该基因降低或调节钾电流IK，从而改变心脏复极。在临床诊断为LQTS的患者中，我们在hERG的N-末端PAS（Per-Arnt-Sim）结构域中鉴定了突变L 69 P。HEK 293细胞中的功能表达表明，仅用突变亚基重建的同源四聚体hERG通道表现出通道蛋白的表面表达显著降低，从而导致hERG电流降低。与hERG-PAS结构域中的许多其他突变不同，L 69 P取代的负面影响不能通过在较低孵育温度下促进蛋白质折叠来挽救。此外，wt和突变体单体的共表达不能恢复wt样表面表达或完整的hERG电流。这些结果表明，L 69 P是一个显性负突变，最有可能发生在蛋白质折叠水平的缺陷，随后抑制运输到质膜。突变通道的功能缺陷支持LQTS的临床诊断。
The congenital long QT syndrome (LQTS) is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram and an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A frequent cause for LQTS is mutations in theKCNH2gene (also known as thehuman ether-a-go-go-related geneorhERG), which reduce or modulate the potassium current IKrand hence alter cardiac repolarization. In a patient with a clinically diagnosed LQTS, we identified the mutation L69P in the N-terminal PAS (Per-Arnt-Sim) domain of hERG. Functional expression in HEK293 cells shows that a homotetrameric hERG channel reconstituted with only mutant subunits exhibits a drastically reduced surface expression of the channel protein thus leading to a diminished hERG current. Unlike many other mutations in the hERG-PAS domain the negative impact of the L69P substitution cannot be rescued by facilitated protein folding at a lower incubation temperature. Further, co-expression of wt and mutant monomers does not restore either wt like surface expression or the full hERG current. These results indicate L69P is a dominant negative mutation, with deficits which most likely occurs at the level of protein folding and subsequently inhibits trafficking to the plasma membrane. The functional deficits of the mutant channel support the clinical diagnosis of a LQTS.