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Early LQT2 nonsense mutation generates N-terminally truncated hERG channels with altered gating properties by the reinitiation of translation

机译：早期的LQT2废话突变通过改变翻译而产生N-末端截短的HERG频道通过改变翻译

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Mutations in the human ether-a-go-go-related gene (hERG) result in long QT syndrome type 2 (LQT2). The hERG gene encodes a K+ channel that contributes to the repolarization of the cardiac action potential. We have previously shown that hERG mRNA transcripts that contain premature termination codon mutations are rapidly degraded by nonsense-mediated mRNA decay (NMD). In this study, we identified a LQT2 nonsense mutation, Q81X, which escapes degradation by the reinitiation of translation and generates N-terminally truncated channels. RNA analysis of hERG minigenes revealed equivalent levels of wild-type and Q81X mRNA while the mRNA expressed from minigenes containing the LQT2 frameshift mutation, P141fs+2X, was significantly reduced by NMD. Western blot analysis revealed that Q81X minigenes expressed truncated channels. Q81X channels exhibited decreased tail current levels and increased deactivation kinetics compared to wild-type channels. These results are consistent with the disruption of the N-terminus, which is known to regulate hERG deactivation. Site-specific mutagenesis studies showed that translation of the Q81X transcript is reinitiated at Met124 following premature termination. Q81X co-assembled with hERG to form heteromeric channels that exhibited increased deactivation rates compared to wild-type channels. Mutant channels also generated less outward current and transferred less charge at late phases of repolarization during ventricular action potential clamp. These results provide new mechanistic insight into the prolongation of the QT interval in LQT2 patients. Our findings indicate that the reinitiation of translation may be an important pathogenic mechanism in patients with nonsense and frameshift LQT2 mutations near the 5′ end of the hERG gene.
机译：人类以太携带相关基因（hERG）中的突变会导致长QT综合征2型（LQT2）。 hERG基因编码一个K + 通道，该通道有助于心脏动作电位的复极化。先前我们已经表明，包含早期终止密码子突变的hERG mRNA转录物会被无义介导的mRNA衰变（NMD）迅速降解。在这项研究中，我们确定了一个LQT2无意义突变Q81X，该突变通过翻译的重新启动而逃脱了降解，并产生了N端截短的通道。 hERG小基因的RNA分析显示，野生型和Q81X mRNA的水平相当，而NMD显着降低了包含LQT2移码突变P141fs + 2X的小基因表达的mRNA。蛋白质印迹分析显示Q81X小基因表达截短的通道。与野生型通道相比，Q81X通道显示出降低的尾电流水平和增加的失活动力学。这些结果与已知调节hERG失活的N端的破坏一致。特定于位点的诱变研究表明，过早终止后，在Met124处重新启动Q81X转录物的翻译。 Q81X与hERG共同组装形成异源通道，与野生型通道相比，该通道显示出更高的失活率。在心室动作电位钳制期间，突变通道在复极化的后期也产生较少的向外电流并转移较少的电荷。这些结果为延长LQT2患者QT间期提供了新的机制。我们的发现表明，翻译的重新启动可能是hERG基因5'端附近无意义和移码LQT2突变的患者的重要致病机制。

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