SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies
SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies
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DOI：
10.1038/ejhg.2015.125
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发表时间：
2016-03-01
影响因子：
5.2
通讯作者：
Van Dooren, Sonia
中科院分区：
文献类型：
--
作者：
Bissay, Veronique;Van Malderen, Sophie C. H.;Van Dooren, Sonia
涉及心脏电压门控肌钠通道（NaV1.5）α亚基的SCN 5A突变导致不同的心脏通道病，具有常染色体显性遗传，如Brugada综合征。另一方面，编码骨骼电压门控钠通道（NaV1.4）的α亚基的SCN 4A中的突变引起非营养不良性肌强直和/或周期性麻痹。在这项研究中，我们调查了心律失常或通道病（如Brugada综合征）是否可以是与SCN 4A变体相关的临床表型的一部分，以及Brugada综合征患者是否存在非营养不良性肌强直或周期性麻痹和相关基因突变。因此，我们筛选了7个家庭与不同的SCN 4A变异和非营养不良性肌强直表型的Brugada综合征，并进行了神经，神经生理和遗传工作的107个Brugada家庭。在SCN 4A相关的非营养不良性肌强直家族中，3例患者临床诊断为Brugada综合征，而我们发现Brugada综合征家族中涉及不同基因的肌强直特征的患病率非常高。一个Brugada家族携带SCN 4A变异，预计可能影响功能，一个家族患有未经遗传学证实的非营养不良性肌强直，一个家族被诊断患有肌强直性营养不良（DMPK基因），一个家族患有先天性肌强直（CLCN 1变异影响功能）。我们的研究结果和数据表明，SCN 4A变异体可能参与自发或药物诱导的1型心电图模式的发展和一些Brugada综合征患者发生恶性心律失常的病理生理机制。
SCN5A mutations involving the alpha-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the alpha-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.