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Abstract：
Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltage-gated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Nav1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na+ current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Nav1.4 channel\'s co-expression with the Navβ4 peptide can generate resurgent Na+ currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na+ currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.
摘要：
先天性肌强直（MC）是一种罕见的疾病，其特征是四肢和躯干肌肉僵硬和无力。据报道，编码电压门控钠通道Nav1.4α亚基的SCN4A基因中的突变是钠通道肌强直（SCM）的原因。Nav1.4通道在骨骼肌中表达，及其相关的信道病影响骨骼肌的兴奋性，可以表现为SCM，副肌强直和周期性瘫痪。在这项研究中,错义突变p.V445M在两个MC家族中被鉴定。为了确定具有突变的Nav1.4通道的功能后果，对转染的中国仓鼠卵巢细胞进行全细胞膜片钳记录.对瞬时Na电流的评估发现，随着突变通道中窗口电流的增加，在激活和失活曲线上都发生了超极化位移。Nav1.4通道与Navβ4肽的共表达可以在去极化后的复极化时产生再生的Na电流。在突变体中，复苏电流的幅度高于野生型（WT）通道。尽管突变通道和WT通道之间的衰变动力学相当，与WT通道相比，突变通道中恢复的Na电流达到峰值的时间显着延长。这些发现表明，Nav1.4通道中的p.V445M突变导致持续和复苏的Na电流增加，这可能有助于重复放电的过度兴奋，并可能促进SCM患者的肌强直复发。
