Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes
Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes
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DOI：
10.1074/jbc.m104471200
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发表时间：
2001-08-17
影响因子：
4.8
通讯作者：
Kass, RS
中科院分区：
文献类型：
--
作者：
Rivolta, I;Abriel, H;Kass, RS
编码心脏钠通道α亚单位的SCN 5A基因缺陷与长QT综合征的长QT-3（LQT-3）亚型和Brugada综合征（BrS）相关。一个先前描述的SCN 5A突变（1795 insD）在C端的结果在临床表型结合QT间期延长和ST段抬高，表明这两种疾病之间的密切关系。在这里，我们提供了额外的证据，这两种疾病是密切相关的。我们报告了在HEK 293细胞中表达的相同密码子Y1795 C（LQT-3）和Y1795 H（BrS）上的两个新突变的分析，并使用全细胞膜片钳程序进行表征。我们发现通道门控的显著和相反的影响与每种临床疾病的细胞基础相关的活性一致。Y1795 H加速失活，Y1795 C减慢失活的开始。Y1795 H突变导致失活的电压依赖性显著负移，但Y1795 C突变不影响失活恢复的动力学。有趣的是，与野生型（WT）通道相比，这两种突变都增加了持续Na+通道活性的表达，尽管这种效应对于Y1795 C突变最为明显，并且这两种突变都促进进入中间或缓慢发展的失活状态。这些数据证实了心脏Na+通道的C-末端尾部在控制通道门控中的关键作用，说明了通道生物物理学的细微变化如何在人类疾病中产生显著和独特的影响，此外，还提供了BrS和LQT-3在分子水平上密切相互关系的进一步证据。
Defects of the SCN5A gene encoding the cardiac sodium channel a-subunit are associated with both the long,QT-3 (LQT-3) subtype of long-QT syndrome and Brugada syndrome (BrS). One previously described SCN5A mutation (1795insD) in the C terminus results in a clinical phenotype combining QT prolongation and ST segment elevation, indicating a close interrelationship between the two disorders. Here we provide additional evidence that these two disorders are closely related. We report the analysis of two novel mutations on the same codon, Y1795C (LQT-3) and Y1795H (BrS), expressed in HEK 293 cells and characterized using whole-cell patch clamp procedures. We find marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder. Y1795H speeds and Y1795C slows the onset of inactivation. The Y1795H, but not the Y1795C, mutation causes a marked negative shift in the voltage dependence of inactivation, and neither mutation affects the kinetics of the recovery from inactivation. Interestingly, both mutations increase the expression of sustained Na+ channel activity compared with wild type (WT) channels, although this effect is most pronounced for the Y1795C mutation, and both mutations promote entrance into an intermediate or a slowly developing inactivated state. These data confirm the key role of the C-terminal tail of the cardiac Na+ channel in the control of channel gating, illustrate how subtle changes in channel biophysics can have significant and distinct effects in human disease, and, additionally, provide further evidence of the close interrelationship between BrS and LQT-3 at the molecular level.