Apart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction, communication and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons. In our present study, we identified an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Nav1.8, which is preferentially expressed in sensory neurons. We expressed both mutations, p.I1511M and p.R512*, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. The results of these experiments reveal that the p.R512* mutation renders the channel non-functional, while the p.I1511M mutation showed only minor effects on the channel’s function. Behavioral experiments in a Nav1.8 loss-of-function mouse model additionally revealed that Nav1.8 may play a role in autism-like symptomatology. Our results present Nav1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights into the genetic basis of this disease.

中文翻译：

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Nav1.8 对自闭症谱系障碍的潜在影响：来自具有复合杂合 SCN10A 突变的先天性病例的证据

自闭症谱系障碍（ASD）除了最突出的症状，即社交互动、沟通和重复行为缺陷外，患者还经常对环境刺激表现出异常的感觉反应。据报道，与健康人相比，特别是潜在疼痛的刺激的体验方式不同。在我们目前的研究中，我们发现一名 ASD 患者的电压门控钠通道 (VGSC) Nav1.8 携带复合杂合突变，该突变优先在感觉神经元中表达。我们在异源表达系统中表达了 p.I1511M 和 p.R512* 这两种突变，并使用膜片钳记录研究了它们的生物物理特性。这些实验的结果表明，p.R512* 突变使通道失去功能，而 p.I1511M 突变仅对通道功能产生轻微影响。Nav1.8 功能丧失小鼠模型的行为实验还表明，Nav1.8 可能在类似自闭症的症状中发挥作用。我们的结果表明 Nav1.8 作为一种可能参与 ASD 病理生理学的蛋白质，因此可能为该疾病的遗传基础提供新的见解。