Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia
Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia
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DOI：
10.1074/jbc.m311953200
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发表时间：
2004-06-25
影响因子：
4.8
通讯作者：
Kimura, A
中科院分区：
文献类型：
--
作者：
Ueda, K;Nakamura, K;Kimura, A
超极化激活的环核苷酸门控通道4基因HCN 4是心脏中在窦房结自律性中起关键作用的起搏通道，并且在一名患有窦房结功能障碍的患者中报告了HCN 4突变。然而，HCN 4在心脏中的表达并不局限于窦房结细胞，而是在其他组织中发现，包括传导系统的细胞。另一方面，另一种心脏离子通道基因SCN 5A的突变也会导致窦房结功能障碍以及其他心律失常，包括长QT综合征、Brugada综合征、特发性心室颤动和进行性心脏传导障碍。这些观察结果表明，HCN 4异常可能参与各种心律失常的发病机制，类似于SCN 5A突变。在这项研究中，我们分析了患有窦房结功能障碍、进行性心脏传导疾病和特发性室颤的患者的HCN 4突变。1例窦房结功能障碍患者出现反复晕厥、心电图QT间期延长、多形性室性心动过速、尖端扭转型室性心动过速，发现错义突变D553N。D553N突变的体外功能研究表明，由于HCN 4通道以显性负性方式的运输缺陷，与If电流降低相关的膜表达降低。这些数据表明，HCN 4功能的丧失与窦房结功能障碍有关，起搏器通道异常的后果可能是QT间期延长和多形性室性心动过速在某些条件下发展的临床特征的基础。
Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.