Nagao Chioko, Okuda Hiroko, Bekker Gert-Jan, Noguchi Atsuko, Takahashi Tsutomu, Koizumi Akio, Youssefian Shohab, Tezuka Tohru, Akioka Shinji
Institute for Protein Research, Osaka University, Osaka, Japan.
Department of Pain Pharmacogenetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Biochem Genet. 2024 Jul 25. doi: 10.1007/s10528-024-10888-1.
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.
家族性发作性疼痛综合征（FEPS）是一种常染色体显性遗传性疾病，其特征为阵发性疼痛发作。FEPS在儿童早期出现，随年龄增长逐渐消失，疲劳、恶劣天气和低温可引发疼痛发作。已报道SCN9A、SCN10A或SCN11A存在多个功能获得性变体，它们分别编码电压门控钠通道α亚基Nav1.7、Nav1.8和Nav1.9。在本研究中，我们对一个四代日本家系进行了基因分析。先证者是一名7岁女孩，她的哥哥、姐姐、母亲和祖母也正在经历或曾经历过疼痛发作，被认为患病。父亲未患病。对先证者的SCN9A、SCN10A和SCN11A进行测序，发现SCN11A有一个新的杂合变体：g.38894937G>A（c.2431C>T，p.Leu811Phe）。该变体在其他患病成员中得到证实，但未在未患病的父亲中发现。受影响的残基Leu811位于Nav1.9的DII/S6螺旋内，对电压传感域的信号转导和孔开放很重要。另一方面，已知c.2432T>C（p.Leu811Pro）变体可导致先天性无痛觉（CIP）。分子动力学模拟表明，p.Leu811Phe增加了Nav1.9的结构稳定性，阻止了必要的构象变化，导致功能所需动力学发生改变。相比之下，与CIP相关的p.Leu811Pro使Nav1.9不稳定。因此，我们推测p.Leu811Phe可能导致电流泄漏，而p.Leu811Pro可增加通过Nav1.9的电流。
