Mechanisms of IKs suppression in LQT1 mutants
Mechanisms of IKs suppression in LQT1 mutants
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DOI：
10.1152/ajpheart.2000.279.6.h3003
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发表时间：
2000-12-01
影响因子：
4.8
通讯作者：
Brown, AM
中科院分区：
文献类型：
--
作者：
Bianchi, L;Priori, SG;Brown, AM
心脏钾离子通道基因KCNQ 1（电压门控性K+通道亚型KvLQT 1）的突变导致LQT 1，这是遗传性长Q-T综合征的最常见类型。KvLQT 1突变通过降低复极化心脏电流[慢延迟整流钾离子电流（I-Ks）]延长Q-T，但是，由于尚不清楚的原因，即使对于相同突变的携带者，临床表型也可能差异很大，这可能解释了遗传模式。目前，仅研究了LQT 1突变体表达的电流，不知道异常亚基是否被转运到细胞表面。在这里，我们第一次检查了KvLQT 1突变的运输，并将结果与表达的I-Ks电流相关联。两个错义突变S225 L和A300 T产生异常电流，另外两个Y281 C和Y315 C不产生电流。然而，在细胞表面检测到所有四种KvLQT 1突变。S225 L、Y281 C和Y315 C对野生型I-Ks电流产生显性负效应，而具有最轻微功能障碍的突变体A300 T则没有。我们研究了严重插入缺失突变体Delta 544的运输，并在细胞表面检测到这种蛋白质。我们比较了细胞和临床表型，发现严重功能失调突变的相关性很差。
Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current (I-Ks)], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I-Ks currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I-Ks current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Delta 544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.