Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome.
Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome.
复制标题
与长 QT 综合征相关的 KCNQ1 基因新突变 (F193L) 的临床和电生理学特征。
作者：
M. Yamaguchi;M. Shimizu;H. Ino;H. Terai;K. Hayashi;H. Mabuchi;N. Hoshi;H. Higashida
KCNQ1是一个编码电压门控心脏K（+）通道α亚基的基因，其特性类似于缓慢激活的延迟整流K（+）电流，是导致长QT综合征（LQTS）的基因之一。然而，KCNQ1基因突变的基因型-表型相关性尚不完全清楚。本研究的目的是鉴定LQTS患者的KCNQ1基因突变，并表征该突变的临床表现和电生理特性。我们通过PCR、单链构象多态性分析和DNA测序对突变进行筛选和鉴定。我们在一个LQTS家族的KCNQ1基因中发现了一个新的突变[Phe193Leu (F193L)]。这种突变的患者表现出轻度影响的表型。先证者是一名17岁的女孩，QT间期延长。她的哥哥、父亲和祖母也有这种突变。他们都没有晕厥病史。在这个家庭中没有发现突然死亡。接下来，我们利用爪蟾卵母细胞表达系统和双微电极电压箝位技术研究了KCNQ1基因F193L突变的电生理特性。与野生型（WT） KCNQ1与水貂联合表达相比，F193L KCNQ1与K（+）通道水貂共表达可抑制峰电流（23.3%）和尾电流（38.2%）。F193L KCNQ1和F193L KCNQ1+minK的电流激活时间常数明显慢于WT KCNQ1和WT KCNQ1+minK。这项电生理研究表明，F193L引起的KCNQ1电流抑制较轻，因此该突变可能导致轻度影响表型。
KCNQ1 is a gene encoding an alpha subunit of voltage-gated cardiac K(+) channels, with properties similar to the slowly activating delayed rectifier K(+) current, and one of the genes causing long QT syndrome (LQTS). However, genotype-phenotype correlations of the KCNQ1 gene mutations are not fully understood. The aims of this study were to identify a mutation in the KCNQ1 gene in patients with LQTS, and to characterize the clinical manifestations and electrophysiological properties of the mutation. We screened and identified mutations by PCR, single-strand conformational polymorphism analysis and DNA sequencing. We identified a novel mutation [Phe193Leu (F193L)] in the KCNQ1 gene in one family with LQTS. The patients with this mutation showed a mildly affected phenotype. The proband was a 17-year-old girl who had a prolonged QT interval. Her elder brother, father and paternal grandmother also had the mutation. None of them had any history of syncope. Sudden death was not found in this family. Next, we studied the electrophysiological characteristics of the F193L mutation in the KCNQ1 gene using the expression system in Xenopus oocytes and the two-microelectrode voltage-clamp technique. Co-expression of F193L KCNQ1 with the K(+) channel minK suppressed peak (by 23.3%) and tail (by 38.2%) currents compared with those obtained by the combination of wild-type (WT) KCNQ1 and minK. Time constants of current activation in F193L KCNQ1 and F193L KCNQ1+minK were significantly slower than those of WT KCNQ1 and WT KCNQ1+minK. This electrophysiological study indicates that F193L causes less severe KCNQ1 current suppression, and thereby this mutation may result in a mildly affected phenotype.