Abstract：
Familial episodic pain syndrome (FEPS) is an autosomal-dominant inherited disorder characterized by paroxysmal pain episodes. FEPS appears in early childhood, gradually disappearing with age, and pain episodes can be triggered by fatigue, bad weather, and cold temperatures. Several gain-of-function variants have been reported for SCN9A, SCN10A, or SCN11A, which encode the voltage-gated sodium channel α subunits Nav1.7, Nav1.8, and Nav1.9, respectively. In this study, we conducted genetic analysis in a four-generation Japanese pedigree. The proband was a 7-year-old girl, and her brother, sister, mother, and grandmother were also experiencing or had experienced pain episodes and were considered to be affected. The father was unaffected. Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel heterozygous variant of SCN11A: g.38894937G>A (c.2431C>T, p.Leu811Phe). This variant was confirmed in other affected members but not in the unaffected father. The affected residue, Leu811, is located within the DII/S6 helix of Nav1.9 and is important for signal transduction from the voltage-sensing domain and pore opening. On the other hand, the c.2432T>C (p.Leu811Pro) variant is known to cause congenital insensitivity to pain (CIP). Molecular dynamics simulations showed that p.Leu811Phe increased the structural stability of Nav1.9 and prevented the necessary conformational changes, resulting in changes in the dynamics required for function. By contrast, CIP-related p.Leu811Pro destabilized Nav1.9. Thus, we speculate that p.Leu811Phe may lead to current leakage, while p.Leu811Pro can increase the current through Nav1.9.
摘要：
家族性阵发性疼痛综合征(FEPS)是一种以阵发性疼痛发作为特征的常染色体显性遗传性疾病。FEPS出现在儿童早期，随着年龄的增长逐渐消失,疼痛发作可以由疲劳引发，恶劣的天气,和寒冷的温度。已经报道了SCN9A的几种功能获得变体，SCN10A,或SCN11A，它们分别编码电压门控钠通道α亚基Nav1.7、Nav1.8和Nav1.9。在这项研究中,我们对一个四代日本家系进行了遗传分析.先证者是个7岁的女孩,还有她哥哥,姐姐,母亲,和祖母也经历或曾经经历过疼痛发作，并被认为受到影响。父亲没有受到影响。SCN9A测序,SCN10A,和先证者中的SCN11A揭示了SCN11A的新杂合变体：g.38894937G>A（c.2431C>T，p.Leu811Phe)。此变体在其他受影响的成员中得到证实，但在未受影响的父亲中未得到证实。受影响的残留物，Leu811位于Nav1.9的DII/S6螺旋内，对于来自电压感应域和孔开口的信号转导很重要。另一方面,c.2432T>C（p。Leu811Pro）变体已知会导致先天性对疼痛不敏感（CIP）。分子动力学模拟表明，p.Leu811Phe增加了Nav1.9的结构稳定性，防止了必要的构象变化，导致功能所需的动力学发生变化。相比之下,CIP相关p.Leu811Pro使Nav1.9不稳定。因此，我们推测p.Leu811Phe可能会导致电流泄漏，而p.Leu811Pro可以通过Nav1.9增加电流。
