PDF(Pubmed)
Abstract：
The voltage-gated sodium channel NaV1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to NaV1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p.V1287I in NaV1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to NaV1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that NaV1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of NaV1.8 p.V1287I are causative for the patient\'s symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of NaV1.8-associated disorders.
摘要：
电压门控钠通道NaV1.8在小口径感觉神经元的体细胞和轴突中显著表达，和相应基因SCN10A的致病变异与外周疼痛和自主神经功能障碍有关。虽然大多数疾病相关的SCN10A变体赋予NaV1.8功能增益特性，导致感觉神经元的过度兴奋，一些通过功能丧失机制影响传入兴奋性。使用全外显子组测序，我们在这里发现了一个罕见的杂合SCN10A错义变异，导致在有15年的远端肢体温度失调逐渐恶化病史的患者中，NaV1.8中p.V1287I的改变。特别是在脚上。进一步的症状包括手指的刺痛和麻木以及出汗增加。为了评估p.V1287I对通道功能的影响，我们进行了电压钳记录，表明该改变赋予了NaV1.8功能的损耗和增益特征，其特征是通道激活和失活的右移电压依赖性。转染的小鼠背根神经节神经元的电流钳记录进一步显示，NaV1.8-V1287I通道拓宽了感觉神经元的动作电位，并增加了它们的放电率，以响应去极化电流刺激，表明杂合环境中变体在细胞水平上的功能获得机制。数据支持以下假设：NaV1.8p.V1287I的特性是患者症状的原因，非疼痛性外周感觉异常应被视为NaV1.8相关疾病临床谱的一部分。
