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 the KCNH2 gene (also known as the human ether-a-go-go-related gene or hERG), which reduce or modulate the potassium current IKr and 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.

中文翻译：

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hERG钾通道的PAS结构域中的L69P突变通过运输缺陷导致LQTS。

先天性长QT综合征（LQTS）是一种心脏疾病，其特点是心电图QT间隔延长，对心律失常和心源性猝死的敏感性增加。导致LQTS的常见原因是KCNH2基因（也称为人类醚相关基因或hERG）中的突变，该突变可降低或调节钾电流IKr，从而改变心脏的复极。在临床诊断为LQTS的患者中，我们在hERG的N端PAS（Per-Arnt-Sim）结构域中鉴定了L69P突变。在HEK293细胞中的功能性表达显示仅用突变亚基重构的同型四聚体hERG通道显示出通道蛋白的表面表达急剧降低，从而导致hERG电流降低。与hERG-PAS域中的许多其他突变不同，L69P取代的负面影响无法通过在较低孵育温度下促进的蛋白质折叠来挽救。此外，wt和突变单体的共表达不能恢复wt如表面表达或完全的hERG电流。这些结果表明L69P是显性的负突变，其缺陷最可能发生在蛋白质折叠的水平，随后抑制了向质膜的运输。突变体通道的功能缺陷支持LQTS的临床诊断。这些结果表明L69P是显性的负突变，其缺陷最可能发生在蛋白质折叠的水平，并随后抑制了向质膜的运输。突变体通道的功能缺陷支持LQTS的临床诊断。这些结果表明L69P是显性的负突变，具有最可能发生在蛋白质折叠水平的缺陷，并随后抑制了向质膜的运输。突变体通道的功能缺陷支持LQTS的临床诊断。