Familial episodic limb pain in kindreds with novel Nav1.9 mutations
Familial episodic limb pain in kindreds with novel Nav1.9 mutations
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DOI：
10.1371/journal.pone.0208516
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发表时间：
2018-12-17
期刊：
影响因子：
3.7
通讯作者：
Koizumi, Akio
中科院分区：
文献类型：
--
作者：
Kabata, Risako;Okuda, Hiroko;Koizumi, Akio
我们以前进行了遗传分析，在六个无关的家庭与婴儿肢体疼痛发作，其特点是冷引起的恶化和缓解在青春期，并报告了两个新的突变p.R222H/S在SCN 11 A负责这些事件。由于在日本没有描述这种综合征（家族性发作性疼痛：FEP）的术语，我们将其命名为。在当前的研究中，我们在2016年3月至2018年3月期间招募了另外42个新的不相关的日本FEP家族，并在SCN 11 A中确定了总共11个突变：7个家族中的p.R222H，以及独立家族中的p.R225C，p.F814C，p.F1146S或p.V1184A。在日本东北地区的FEP患者中，已证实经常观察到一种创始者突变SCN 11 A p.R222 H。我们还鉴定了SCN 11 A的两个新的错义变体，p.F814C和p.F1146S。为了评估后两种突变的影响，我们产生了含有p.F802C（F802 C）和p.F1125S（F1125 S）（分别是人p.F814C和p.F1146S的直系同源物）的敲入小鼠模型。然后，我们使用从6-8周龄小鼠身上解剖的背根神经节神经元进行电生理研究。与WT小鼠相比，F802 C和F1125 S小鼠的解剖神经元在高输入电流刺激下表现出静息膜电位和动作电位（AP）放电频率的增加。此外，激发概率诱发AP增加低刺激输入F1125 S小鼠，而几个AP参数和电流阈值没有显着差异的突变和WT小鼠之间。这些结果表明F802 C或F1125 S小鼠的兴奋性水平高于WT小鼠，并表明这些新突变是功能获得突变。可以预期，相当数量的潜在FEP患者可能是SCN 11 A突变获得功能的结果。
We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p. V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p. F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6-8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input-current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.