Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias
Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias
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DOI：
10.1093/hmg/6.11.1943
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发表时间：
1997-10-01
影响因子：
3.5
通讯作者：
Jentsch, TJ
中科院分区：
文献类型：
--
作者：
Wollnik, B;Schroeder, BC;Jentsch, TJ
遗传性长QT综合征（LQTS），其特征是心电图QT间期延长和心律失常，是由至少四种不同基因的突变引起的，其中三种基因已被鉴定并编码心脏离子通道。LQTS最常见的形式是由于钾通道基因KVLQT1的突变，但它们对相关电流的影响仍不清楚。KVLQT1的不同突变导致显性罗马诺-沃德（RW）综合征和隐性罗马诺-沃德（RW）综合征Jervell 和 Lange-Nielsen (JLN) 综合征，除了心脏异常之外，还包括先天性耳聋，K(V)LQT1 与 IsK 蛋白的共表达会引发缓慢激活的钾电流，类似于心脏 I-ks 电流。我们现在表明，IsK 不仅改变 K(V)LQT1 电流的动力学，而且改变其离子选择性。在 RW 中发现了几种突变，包括一种新的突变 (D222N)通过显性失活机制消除通道活性并降低野生型K(V)LQT1的活性，相比之下，截断K(V)LQT1通道蛋白羧基末端的JLN突变废除了通道功能而不具有显性失活效应，这充分解释了不同的遗传模式。此外，我们鉴定了K(V)LQT1基因的一种新的剪接变体，但无法实现功能性该表达或先前描述的心脏特异性亚型的表达。
The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels, The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown, Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness, Coexpression of K(V)LQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac I-ks current, We now show that IsK not only changes the kinetics of K(V)LQT1 currents, but also its ion selectivity, Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type K(V)LQT1 by a dominant-negative mechanism, By contrast, a JLN mutation truncating the carboxy-terminus of the K(V)LQT1 channel protein abolishes channel function without having a dominant-negative effect, This fully explains the different patterns of inheritance, Further, we identified a novel splice variant of the K(V)LQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.