Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several the pore-forming voltage-gated sodium channel α subunits (Na_Vs) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate Na_V trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly-identified Y69H variant of the β2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.

中文翻译：

---

特发性小纤维神经病中一种新的功能获得性钠通道β2亚基突变

小纤维神经病 (SFN) 是一种影响薄髓 Aδ 纤维和无髓 C 纤维的常见疾病，通常会导致极度疼痛和自主神经功能障碍。SFN 与几种情况有关，但大量病例没有明显的原因。最近的遗传学研究已经在 SFN 患者的一个子集中发现了几个成孔电压门控钠通道 α 亚基 (Na _V s) 的潜在致病性功能获得性突变，但辅助钠通道 β 亚基的影响较小在疾病的发展过程中。β亚基调节 Na _V贩运和门控，以及一些突变与癫痫和心功能不全有关。最近，我们首次提供了 β2 亚基突变对人类疼痛性糖尿病神经病变疼痛的贡献的第一个证据。在这里，我们提供了钠通道 β 亚基突变参与 SFN 发病机制的第一个证据，没有其他已知原因。我们通过电流钳分析表明，新发现的 β2 亚基 Y69H 变体可诱导背根神经节神经元的神经元过度兴奋，降低动作电位放电的阈值并允许增加重复动作电位尖峰。在 β2-Y69H 变体诱导的过度兴奋的基础上，我们证明了河豚毒素敏感但不是河豚毒素抗性钠电流的上调。