Genotype-Phenotype Correlations of KCNJ2 Mutations in Japanese Patients With Andersen-Tawil Syndrome
Genotype-Phenotype Correlations of KCNJ2 Mutations in Japanese Patients With Andersen-Tawil Syndrome
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DOI：
10.1002/humu.9483
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发表时间：
2007-02-01
期刊：
影响因子：
3.9
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Haruna, Yoshisumi;Kobori, Atsushi;Horie, Minoru
Andersen-Tawil综合征（ATS）是一种罕见的遗传性疾病，以周期性麻痹、轻度畸形、心电图QT间期延长伴室性心律失常为特征。编码人类内向整流钾通道Kir 2.1的KCNJ 2突变已在ATS患者中鉴定。我们的目的是澄清ATS患者的基因型-表型相关性。我们筛选了23例临床诊断的ATS患者从13个无关的日本家庭。在本研究纳入的23例ATS患者中鉴定了10种不同形式的KCNJ 2突变。心电图均显示QTc间期正常，U波异常，伴QUc延长及多种室性心律失常。其中双向室性心动过速（VT）发生率为57%（13/23）。23名携带者中有13名（57%）出现周期性麻痹，17名（74%）出现畸形特征，4名（17%）在婴儿期出现癫痫发作。两种新型KCNJ 2突变（c.200G>A（p.R67Q）和c.436G>A（p.G146S））的功能测定显示，在异源表达系统中没有功能性内向整流电流，并且当与野生型KCNJ 2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下分别降低91%和84%）。免疫细胞化学和共聚焦成像显示正常的突变通道的贩运。在我们的研究中，所有临床诊断的ATS患者都有KCNJ 2突变，并且在典型的心脏表型方面表现出较高的突变率：主要的U波和室性心律失常，通常是双向VT。(C)2007 Wiley-Liss，Inc.
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. (C) 2007 Wiley-Liss, Inc.