A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly
A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly
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DOI：
10.1093/emboj/19.3.332
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发表时间：
2000-02-01
期刊：
影响因子：
11.4
通讯作者：
Pongs, O
中科院分区：
文献类型：
--
作者：
Schmitt, N;Schwarz, M;Pongs, O
LQT1基因座(KCNQ1)与最常见的遗传性长QT(LQT)综合征相关。LQT患者有突触发作和猝死的高风险。KCNQ1基因编码KvLQT1α亚基，KvLQT1α亚基与辅助的ISK(KCNE1，水貂)亚基一起形成IKS K+通道，突变的KvLQT1亚基可能与常染色体显性遗传性LQT相关，即Romano-Ward综合征，也可能与常染色体隐性遗传性Jervell和Lange-Nielsen综合征(JLNS)相关。我们已经在KvLQT1 C-末端的589-620残基之间确定了一个小的结构域，它可能作为KvLQT1亚基的组装结构域，KvLQT1 C-末端不组装，KvLQT1亚基不表达功能K+通道。我们发现，KvLQT1残基544处的JLN缺失-插入突变消除了C末端组装结构域的重要部分。因此，JLN突变体可能存在KvLQT1亚基组装缺陷，这一结果为临床观察JLN杂合子携带者表现轻度心功能障碍和严重JLNS表型以KvLQT1通道缺失为特征提供了分子基础。
The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IKs K+ channels, Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits, KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K+ channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly, The results pro,ide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel.