Bianchi L, Priori S G, Napolitano C, Surewicz K A, Dennis A T, Memmi M, Schwartz P J, Brown A M
The Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3003-11. doi: 10.1152/ajpheart.2000.279.6.H3003.
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 Delta544 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.
心脏钾离子通道基因KCNQ1（电压门控钾离子通道亚型KvLQT1）的突变会导致LQT1，这是遗传性长Q-T综合征最常见的类型。KvLQT1突变通过降低复极化心脏电流[缓慢延迟整流钾电流（I(Ks)）]来延长Q-T间期，但由于尚不明确的原因，即使对于相同突变的携带者，临床表型也可能有很大差异，这或许可以解释其遗传模式。目前，仅对LQT1突变体表达的电流进行了研究，而异常亚基是否转运至细胞表面尚不清楚。在此，我们首次检测了KvLQT1突变的转运情况，并将结果与所表达的I(Ks)电流进行关联。两个错义突变S225L和A300T产生了异常电流，另外两个突变Y281C和Y315C则未产生电流。然而，所有四个KvLQT1突变均在细胞表面被检测到。S225L、Y281C和Y315C对野生型I(Ks)电流产生显性负效应，而功能障碍最轻的突变体A300T则没有。我们检测了严重的插入缺失突变体Delta544的转运情况，同样在细胞表面检测到了该蛋白。我们比较了细胞表型和临床表型，发现严重功能障碍的突变之间相关性较差。
