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タイトル: Familial episodic limb pain in kindreds with novel Nav1.9 mutations
著者: Kabata, Risako
Okuda, Hiroko
Noguchi, Atsuko
Kondo, Daiki
Fujiwara, Michimasa
Hata, Kenichiro
Kato, Yoshifumi
Ishikawa, Ken
Tanaka, Manabu
Sekine, Yuji
Hishikawa, Nozomi
Mizukami, Tomoyuki
Ito, Junichi
Akasaka, Manami
Sakurai, Ken
Yoshida, Takeshi
Minoura, Hironori
Hayashi, Takashi
Inoshita, Kohei
Matsuyama, Misayo
Kinjo, Noriko
Cao, Yang
Inoue, Sumiko
Kobayashi, Hatasu
Harada, Kouji H.
Youssefian, Shohab
Takahashi, Tsutomu
Koizumi, Akio
著者名の別形: 加畑, 理咲子
奥田, 裕子
吉田, 健司
井上, 純子
原田, 浩二
小泉, 昭夫
発行日: 17-Dec-2018
出版者: Public Library of Science (PLoS)
誌名: PLOS ONE
巻: 13
号: 12
論文番号: e0208516
抄録: 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”小児四肢疼痛発作症”. 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.
著作権等: © 2018 Kabata 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/2433/236014
DOI(出版社版): 10.1371/journal.pone.0208516
PubMed ID: 30557356
出現コレクション:学術雑誌掲載論文等

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