Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk
Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk
复制标题
DOI：
10.1016/s0008-6363(99)00411-3
复制
发表时间：
2000-03-01
影响因子：
10.8
通讯作者：
Barhanin, J
中科院分区：
文献类型：
--
作者：
Chouabe, C;Neyroud, N;Barhanin, J
目的：我们报告了四个KCNQ 1突变的功能表达，这些突变影响精氨酸残基并导致Romano-Ward（RW）和Jervell和Lange-Nielsen（JLN）先天性长QT综合征。结果：R539 W和R190 Q突变存在于典型的RW家系中，为常染色体显性遗传。R243 H突变在一个复合杂合子JLN患者中发现，该患者表现为耳聋和心脏症状。第四个突变R533 W是一个新的隐性RW综合征病例，因为纯合子携带者出现晕厥但没有耳聋，而杂合子携带者则无症状。R190 Q突变未能产生功能性同源通道。R243 H、R533 W和R539 W突变诱导通道激活的正电压偏移，但仅当与IsK共表达时，指出这些带正电荷的残基在IsK调节KvLQT 1的门控特性中的关键作用。R533 W诱导的正位移仅为15%。这种小的影响是兼容的RW表型传递的隐性性状。平均QTc明显延长（P
Objectives: We report the functional expression of four KCNQ1 mutations affecting arginine residues and resulting in Romano-Ward (RW) and the Jervell and Lange-Nielsen (JLN) congenital long QT syndromes. Results: The R539W and R190Q mutations were found in typical RW families with an autosomal dominant transmission. The R243H mutation was found in a compound heterozygous JLN patient who presents with deafness and cardiac symptoms. The fourth mutation, R533W, was a new case of recessive form of the RW syndrome since homozygous carriers experienced syncopes but showed no deafness, whereas the heterozygous carriers were asymptomatic. The R190Q mutation failed to produce functional homomeric channels. The R243H, R533W and R539W mutations induced a positive voltage shift of the channel activation but only when co-expressed with IsK, pointing out the critical role of these positively charged residues in the modulation of the gating properties of KvLQT1 by IsK. The positive shift induced by R533W was merely 15%. This small effect was compatible with the recessive character of the RW phenotype transmission. The average QTc was significantly longer (P