Cardiac sodium channel mutations: why so many phenotypes?
Cardiac sodium channel mutations: why so many phenotypes?
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DOI：
10.1038/nrcardio.2014.85
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Dudley SC Jr
中科院分区：
文献类型：
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作者：
Liu M;Yang KC;Dudley SC Jr
心脏钠通道（Nav1.5）的突变可引起通道功能的获得或丧失。功能获得突变可引起长QT综合征3型和可能的心房颤动，而功能丧失突变与多种表型相关，如Brugada综合征、心传导疾病、病态窦综合征，以及可能的扩张性心肌病。Nav1.5突变产生的表型根据突变对通道生物物理的直接影响而变化，但也与年龄、性别、体温和心脏区域之间有关。这种表型变异性使得基因型-表型相关性变得困难。在这篇展望文章中，我们提出，不归因于通道功能突变依赖性变化的表型变异可能是通道行为的其他修饰因子的结果，例如转录、RNA加工、翻译、翻译后修饰和蛋白质降解中的其他遗传变异和改变。考虑这些修饰因子可能有助于改善基因型-表型相关性，并导致新的治疗策略。
Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies.