Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.
Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.
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DOI：
10.1371/journal.pone.0154827
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Koizumi A
中科院分区：
文献类型：
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作者：
Okuda H;Noguchi A;Kobayashi H;Kondo D;Harada KH;Youssefian S;Shioi H;Kabata R;Domon Y;Kubota K;Kitano Y;Takayama Y;Hitomi T;Ohno K;Saito Y;Asano T;Tominaga M;Takahashi T;Koizumi A
疼痛性周围神经病变与感觉神经元中的各种电压门控钠通道突变相关。最近Nav1.9，电压门控钠通道亚型，已被确定为某些外周疼痛综合征的遗传影响。在这项研究中，我们进行了一项遗传研究，在六个无关的多代日本家庭与发作性疼痛综合征。受影响的参与者（n = 23）的特点是婴儿复发性疼痛发作与青春期左右的自发缓解。这种独特的表型以常染色体显性模式遗传。对两个家系的12名患病成员和9名未患病成员进行了连锁分析，在3 p22上鉴定出一个单一位点（LOD得分为4.32）。外显子组分析（n = 14）进行了影响和未受影响的成员在这两个家庭和一个额外的家庭。在SCN 11 A中鉴定了两种错义变体：R222 H和R222 S。接下来，我们产生了携带突变之一（R222 S）的敲入小鼠模型。使用R222 S和野生型C57 BL/6（WT）小鼠，年轻（8-9周龄;每组n = 10-12）和成熟（36-38周龄;每组n = 5-6）的行为测试（Hargreaves测试和冷板测试）显示，R222 S小鼠比WT小鼠对热和冷刺激显著（p < 0.05）更敏感。使用8-9周龄小鼠背根神经节神经元的电生理研究显示，静息膜电位无显著差异，但与WT小鼠相比，R222 S小鼠的诱发动作电位的输入阻抗和放电频率显著增加。然而，在Nav1.9（WT、R222 S和R222 H）过表达的ND 7/23细胞系之间没有显著差异。这些结果表明，我们的新突变是一种功能获得性突变，导致婴儿家族性发作性疼痛。在此开发的小鼠模型将用于与SCN 11 A突变相关的家族性发作性疼痛综合征的药物筛选。
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8–9 weeks old; n = 10–12 for each group) and mature (36–38 weeks old; n = 5–6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8–9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.