Splawski I, Tristani-Firouzi M, Lehmann M H, Sanguinetti M C, Keating M T
Department of Human Genetics, University of Utah, Salt Lake City 84112, USA.
Nat Genet. 1997 Nov;17(3):338-40. doi: 10.1038/ng1197-338.
Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes. Despite their functional importance, dysfunction of potassium-channel beta-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes beta-subunits (hminK) that co-assemble with KvLQT1 alpha-subunits to form the slowly activating delayed rectifier K+ (IKs) channel. Because KVLQT1 mutations cause arrhythmia susceptibility in the long QT syndrome (LQT), we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKs by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKs channel.
离子通道β亚基是辅助蛋白，与α亚基共同组装以调节门控动力学并增强多聚体通道复合物的稳定性。尽管它们在功能上很重要，但钾通道β亚基功能障碍尚未与疾病相关联。最近的生理学研究表明，KCNE1编码与KvLQT1α亚基共同组装形成缓慢激活延迟整流钾离子（IKs）通道的β亚基（hminK）。由于KVLQT1突变会导致长QT综合征（LQT）患者易患心律失常，我们推测KCNE1突变也会导致这种疾病。在此，我们确定了两个LQT家族中受影响成员的KCNE1错义突变。这两个突变（S74L、D76N）通过改变激活的电压依赖性和加速通道失活来降低IKs。D76N hminK还具有强烈的显性负效应。这些突变的功能后果将是心脏复极延迟和心律失常风险增加。这是首次将KCNE1描述为LQT基因，并证实hminK是IKs通道的组成蛋白。
