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Title: Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.
Authors: Okuda, Hiroko
Noguchi, Atsuko
Kobayashi, Hatasu kyouindb researcher_resolver
Kondo, Daiki
Harada, Kouji H
Youssefian, Shohab
Shioi, Hirotomo
Kabata, Risako
Domon, Yuki
Kubota, Kazufumi
Kitano, Yutaka
Takayama, Yasunori
Hitomi, Toshiaki
Ohno, Kousaku
Saito, Yoshiaki
Asano, Takeshi
Tominaga, Makoto
Takahashi, Tsutomu
Koizumi, Akio kyouindb researcher_resolver
Author's alias: 奥田, 裕子
野口, 篤子
小林, 果
原田, 浩二
小泉, 昭夫
Issue Date: 25-May-2016
Publisher: Public Library of Science
Journal title: PLOS ONE
Volume: 11
Issue: 5
Thesis number: e0154827
Abstract: 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.
Description: 乳幼児期に特異的な手足の痛み発作を起こす病気を見つけ原因を解明 -この病気を小児四肢疼痛発作症と命名-. 京都大学プレスリリース. 2016-05-27.
Rights: © 2016 Okuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/214280
DOI(Published Version): 10.1371/journal.pone.0154827
PubMed ID: 27224030
Related Link: http://www.kyoto-u.ac.jp/ja/research/research_results/2016/160527_1.html
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