首页> 外文期刊>Journal of Electrocardiology: An International Publication for the Study of the Electrical Activities of the Heart >Ambigous phenotipic expression of some mutations in the cardiac Nav1.5 sodium channel
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Ambigous phenotipic expression of some mutations in the cardiac Nav1.5 sodium channel

机译:心脏NAV1.5钠通道中一些突变的模糊表型表达

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Introduction Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since 1995, hundreds of mutations have been found in more than twenty genes coding for cardiac ion channel subunits or proteins regulating cardiac ion channels. The main ECG syndromes caused by those mutations are outlined but there are many mixed and intermediate phenotypes. The phenotype-genotype correlations are not well understood but expected to be related to a functional effect on the ion conductivity. Material and methods Clinical examination including family history taking, ECG, 24-h Holter monitoring, and pharmacological testing with Na + -blockers (by indication) was performed for 192 families with suspected primary arrhythmic syndromes. Diagnoses were established using conventional criteria. Genetic screening of KCNQ1 , KCNE1 , KCNH2 , KCNE2 , KCNJ2 , KCNE3 , SCN5A , and SCN1B-SCN4B was performed for 192 probands by bi-directional Sanger sequencing. Phenotype-genotype correlations had been analyzed. Results and discussion Totally we had found 58 mutations in the genes encoding potassium channels (39 in the KCNQ1 gene, 14 in the KCNH2 gene, 2 in the KCNE1 gene, 1 in the KCNE2, and 1 in the KCNJ2 gene) and 23 mutations in the genes encoding sodium channels (22 in the SCN5A and 1 on the SCN1B). Most of mutations were found in a single family. Patients caring two mutations had more sever clinical appearance of cardiac arrhythmia and high risk of cardiac sudden death. We had found 5 mutations encoding sodium channel mutations (4 in the SCN5A gene and 1 in the SCN1B gene), which lead to the different and sometimes opposite phenotypes in different probands (LQTS and/or BrS, IVF, various cardiomyopathies) or even within the same family members. This phenomenon was not observed in clinical expression of the potassium channel mutations. All mutations found in the genes encoding potassium channels subunits had univocal and predictable phenotype. Mutations leading to the haplo-insufficiency or “loss-of-function” of the potassium channels had caused Long QT Syndrome; “gain-of-function” mutations were responsible for Short QT Syndrome and/or Brugada Syndrome. Conclusion Despite the fairly detailed biophysical characterizations of the mutant variants of Nav1.5 protein, the stages of the molecular pathogenesis leading from the disruption of sodium conductance to the clinical phenotype are not fully understood. ?Non-canonical? functions of the Nav1.5 channel beside ion conductance might be crucial for the resulting clinical appearance.
机译:介绍遗传性心脏心律失常综合征是涉及离子通道的最多研究的人类障碍之一。自1995年以来,已经发现了数百个突变,其在20多个基因编码用于心脏离子通道亚基或调节心脏离子通道的蛋白质。由这些突变引起的主要心电图综合征概述,但有许多混合和中间表型。表型基因型相关性并不很好地理解,但预期与对离子电导率的功能影响有关。材料和方法临床检查包括家族历史,ECG,24-H HOLTER监测和具有Na + -Blockers(通过指示)的药理检测,对192个具有疑似原发性心律失常综合征的家族进行。使用常规标准建立诊断。通过双向Sanger测序对KCNQ1,KCNE1,KCNH2,KCNE2,KCNJ2,KCNE3,SCN5A和SCN1B-SCN4B进行遗传筛选。已经分析了表型基因型相关性。结果和讨论完全我们发现了在编码钾通道的基因中发现了58个突变(在KCNQ1基因中的39中,在KCNE1基因中的14个中,kCne1基因2中的2中,KCNE2中的1个,1中的1中的1中)和23个突变编码钠通道的基因(SCN5A和SCN1B上的1中的22)。大部分突变都在一个家庭中发现。关心两个突变的患者在心律失常的临床外观中具有更多的临床外观和心脏猝死的高风险。我们发现5种编码钠通道突变的5个突变(SCN5A基因中的4个,SCN1B基因中的1个),这导致不同的证书(LQT和/或BRS,IVF,各种心肌病)甚至内部的不同且有时相反的表型同一个家庭成员。在钾通道突变的临床表达中未观察到这种现象。编码钾通道亚基的基因中发现的所有突变具有本质和可预测的表型。导致钾通道的淘汰空气功能不全或“功能失去”的突变造成了长QT综合征; “功能性”突变对短QT综合征和/或布鲁加达综合征负责。结论尽管Nav1.5蛋白的突变体变体的相当详细的生物物理表征,但不完全理解从临床表型的破坏引起的分子发病机制的阶段。 ?非规范?离子电导旁边的NAV1.5通道的功能对于所产生的临床外观可能是至关重要的。

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