A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations.
A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations.
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DOI：
10.1016/j.hrthm.2010.11.034
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发表时间：
2011-03
期刊：
影响因子：
5.5
通讯作者：
Deschenes, Isabelle
中科院分区：
文献类型：
--
作者：
Shinlapawittayatorn, Krekwit;Du, Xi X.;Liu, Haiyan;Ficker, Eckhard;Kaufman, Elizabeth S.;Deschenes, Isabelle
心脏钠通道基因SCN5A的缺陷可引起广泛的遗传性心律失常综合征。对1例晕厥先证者进行基因分型后，鉴定出SCN5A突变体P2006A和常见多态性H558R。本研究的主要目的是确定SCN5A-H558R多态性是否可以改变P2006A突变中观察到的缺陷门控动力学，从而解释为什么在对照人群中发现了这种功能获得性突变。突变采用定点诱变技术，在HEK293细胞中短暂异源表达。采用全细胞膜片钳技术在室温下测量全细胞钠电流。在HEK293细胞中，P2006A表现出与长QT综合征典型相关的生物物理缺陷，通过增加持续钠电流，在失活的电压依赖性中产生去极化位移，并加速失活后的恢复。有趣的是，当在相同或不同基因上共表达时，P2006A和H558R表现出与野生型（WT）相似的电流。我们还研究了H558R是否可以调节其他SCN5A突变的门控缺陷。有趣的是，H558R多态性还将SCN5A突变V1951L的门控缺陷恢复到WT水平。我们的研究结果表明，H558R可能在通道快速失活的稳定中发挥重要作用，并可能为P2006A功能获得突变在控制人群中被发现提供合理的解释。我们的结果也提示SCN5A多态性H558R可能是一种疾病修饰基因。
Defects in the cardiac sodium channel gene, SCN5A, can cause a broad spectrum of inherited arrhythmia syndromes. After genotyping of a proband who presented with syncope, the SCN5A mutant P2006A and the common polymorphism H558R were identified. The main objective of this study was to determine whether the SCN5A-H558R polymorphism could modify the defective gating kinetics observed in the P2006A mutation and therefore explain why this gain-of-function mutation has been identified in control populations. Mutations were engineered using site directed mutagenesis and heterologously expressed transiently in HEK293 cells. Whole-cell sodium currents were measured at room temperature using the whole-cell patch clamp technique. In HEK293 cells, P2006A displayed biophysical defects typically associated with long QT syndrome by increasing persistent sodium current, producing a depolarizing shift in voltage dependence of inactivation, and hastening recovery from inactivation. Interestingly, when co-expressed either on the same or different genes, P2006A and H558R displayed currents that behaved like wild-type (WT). We also investigated whether H558R can modulate the gating defects of other SCN5A mutations. Interestingly, the H558R polymorphism also restored the gating defects of the SCN5A mutation V1951L to the WT level. Our results suggest that H558R might play an important role in stabilization of channel fast inactivation and may provide a plausible explanation as to why the P2006A gain-of-function mutation has been identified in control populations. Our results also suggest that the SCN5A polymorphism H558R might be a disease modifying gene.
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