Sottas Valentin, Abriel Hugues
Department of Clinical Research, Ion Channel Research Group, University of Bern, Switzerland.
Department of Clinical Research, Ion Channel Research Group, University of Bern, Switzerland.
Biochim Biophys Acta. 2016 Jul;1863(7 Pt B):1791-8. doi: 10.1016/j.bbamcr.2016.02.013. Epub 2016 Feb 22.
During the past two decades, many pathological genetic variants in SCN5A, the gene encoding the pore-forming subunit of the cardiac (monomeric) sodium channel Na(v)1.5, have been described. Negative dominance is a classical genetic concept involving a "poison" mutant peptide that negatively interferes with the co-expressed wild-type protein, thus reducing its cellular function. This phenomenon has been described for genetic variants of multimeric K(+) channels, which mechanisms are well understood. Unexpectedly, several pathologic SCN5A variants that are linked to Brugada syndrome also demonstrate such a dominant-negative (DN) effect. The molecular determinants of these observations, however, are not yet elucidated. This review article summarizes recent findings that describe the mechanisms underlying the DN phenomenon of genetic variants of K(+), Ca(2+), Cl(-) and Na(+) channels, and in particular Brugada syndrome variants of Na(v)1.5. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
在过去二十年中，已描述了许多编码心脏（单体）钠通道Na(v)1.5孔形成亚基的基因SCN5A中的病理性遗传变异。负显性是一个经典的遗传概念，涉及一种“毒性”突变肽，它对共表达的野生型蛋白产生负面干扰，从而降低其细胞功能。这种现象已在多聚体K(+)通道的遗传变异中被描述，其机制已得到充分理解。出乎意料的是，一些与Brugada综合征相关的病理性SCN5A变异也表现出这种显性负效应（DN）。然而，这些观察结果的分子决定因素尚未阐明。这篇综述文章总结了最近的研究发现，这些发现描述了K(+)、Ca(2+)、Cl(-)和Na(+)通道遗传变异，特别是Na(v)1.5的Brugada综合征变异的DN现象背后的机制。本文是名为：心肌细胞生物学：心脏发育和环境线索的整合的特刊的一部分，由Marcus Schaub和Hughes Abriel编辑。
