Haruna Yoshisumi, Kobori Atsushi, Makiyama Takeru, Yoshida Hidetada, Akao Masaharu, Doi Takahiro, Tsuji Keiko, Ono Seiko, Nishio Yukiko, Shimizu Wataru, Inoue Takehiko, Murakami Tomoaki, Tsuboi Naoya, Yamanouchi Hideo, Ushinohama Hiroya, Nakamura Yoshihide, Yoshinaga Masao, Horigome Hitoshi, Aizawa Yoshifusa, Kita Toru, Horie Minoru
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hum Mutat. 2007 Feb;28(2):208. doi: 10.1002/humu.9483.
Andersen-Tawil syndrome (ATS) is a rare inherited disorder characterized by periodic paralysis, mild dysmorphic features, and QT or QU prolongation with ventricular arrhythmias in electrocardiograms (ECGs). Mutations of KCNJ2, encoding the human inward rectifying potassium channel Kir 2.1, have been identified in patients with ATS. We aimed to clarify the genotype-phenotype correlations in ATS patients. We screened 23 clinically diagnosed ATS patients from 13 unrelated Japanese families. Ten different forms of KCNJ2 mutations were identified in the 23 ATS patients included in this study. Their ECGs showed normal QTc intervals and abnormal U waves with QUc prolongation and a variety of ventricular arrhythmias. Especially, bidirectional ventricular tachycardia (VT) was observed in 13 of 23 patients (57%). Periodic paralysis was seen in 13 of 23 carriers (57%), dysmorphic features in 17 (74%), and seizures during infancy in 4 (17%). Functional assays for the two novel KCNJ2 mutations (c. 200G>A (p. R67Q) and c. 436G>A (p. G146S)) displayed no functional inward rectifying currents in a heterologous expression system and showed strong dominant negative effects when co-expressed with wild-type KCNJ2 channels (91% and 84% reduction at -50 mV respectively compared to wild-type alone). Immunocytochemistry and confocal imaging revealed normal trafficking for mutant channels. In our study, all of the clinically diagnosed ATS patients had KCNJ2 mutations and showed a high penetrance with regard to the typical cardiac phenotypes: predominant U wave and ventricular arrhythmias, typically bidirectional VT.
安德森-塔维尔综合征（ATS）是一种罕见的遗传性疾病，其特征为周期性麻痹、轻度畸形特征以及心电图（ECG）显示QT或QU间期延长并伴有室性心律失常。编码人类内向整流钾通道Kir 2.1的KCNJ2基因突变已在ATS患者中被发现。我们旨在阐明ATS患者的基因型-表型相关性。我们对来自13个无关日本家庭的23例临床诊断为ATS的患者进行了筛查。在本研究纳入的23例ATS患者中鉴定出10种不同形式的KCNJ2突变。他们的心电图显示QTc间期正常，U波异常，QUc间期延长以及多种室性心律失常。特别是，23例患者中有13例（57%）观察到双向室性心动过速（VT）。23例携带者中有13例（57%）出现周期性麻痹，17例（74%）有畸形特征，4例（17%）在婴儿期出现癫痫发作。对两种新的KCNJ2突变（c. 200G>A（p. R67Q）和c. 436G>A（p. G146S））的功能分析显示，在异源表达系统中无功能性内向整流电流，并且与野生型KCNJ2通道共表达时显示出强烈的显性负效应（与单独的野生型相比，在-50 mV时分别降低91%和84%）。免疫细胞化学和共聚焦成像显示突变通道的转运正常。在我们的研究中，所有临床诊断为ATS的患者都有KCNJ2突变，并且在典型心脏表型方面具有高外显率：主要为U波和室性心律失常，典型的是双向VT。
