Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome
Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome
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DOI：
10.1161/circep.107.748103
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发表时间：
2008-08-01
影响因子：
8.4
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Delpon, Eva;Cordeiro, Jonathan M.;Antzelevitch, Charles
背景-Brugada综合征是一种与心脏骤停发生率高相关的遗传性综合征，与4种不同基因的突变有关，导致钠和钙通道活性丧失。虽然瞬时外向电流（I-to）被认为在综合征的表达中发挥了重要作用，但I-to相关基因的突变尚未被确定，采用单链构象多态性电泳和直接测序技术对105例Brugada综合征先证者进行了离子通道基因突变筛查。1例先证者KCNE 3（MiRP 2）基因发生错义突变（R99 H）。4/4表型阳性和0/3表型阴性的家系成员发现R99 H突变。使用野生型（WT）或突变型KCNE 3和WT KCND 3或KCNQ 1共转染中国仓鼠卵巢-K1细胞。48小时后进行全细胞膜片钳研究。在人心房样本的免疫共沉淀实验中分析了Kv4.3和KCNE 3之间的相互作用。共转染R99 H-KCNE 3与KCNQ 1没有产生尾电流大小或动力学的改变。然而，与WT KCNF-3+ KCND 3相比，R99 H KCNE 3与KCND 3共转染导致I-to强度显著增加。使用组织分离的左心耳的人的心脏，我们也表明，Kv4.3和KCNE 3可以coimmunoprecipitated.Conclusions-These结果提供了明确的证据，KCNE 3的功能作用的调制的I-到在人类心脏，并表明，KCNE 3突变的基础发展的Brugada综合征。(Circ心律失常电生理学2008;1：209-218）。
Background-The Brugada syndrome, ail inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I-to) is thought to play a prominent role in the expression of the syndrome, mutations in I-to-related genes have not been identified as yet.Methods and Results-One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H-KCNE3 with KCNQ1 produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I-to intensity compared with WT KCNF-3+KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that Kv4.3 and KCNE3 can be coimmunoprecipitated.Conclusions-These results provide definitive evidence for a functional role of KCNE3 in the modulation of I-to in the human heart and suggest that mutations in KCNE3 can underlie the development of the Brugada syndrome. (Circ Arrhythmia Electrophysiol. 2008;1:209-218.)