2018 Fiscal Year Final Research Report
Functional analysis of novel mutations of SCN11A for future drug of familial episodic pain
| Project/Area Number |
15K08772
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hygiene and public health
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| Research Institution | Kyoto University |
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Principal Investigator |
Okuda Hiroko 京都大学, 医学研究科, 特定助教 (30709663)
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| Co-Investigator(Kenkyū-buntansha) |
小泉 昭夫 京都大学, 医学研究科, 名誉教授 (50124574)
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| Research Collaborator |
TAKAHASHI Tsutomu
NOGUCHI Atsuko
HARADA Kouji
YOUSSEFIAN Shohab
HITOMI Toshiaki
KOBAYASHI Hatasu
KABATA Risako
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | 小児四肢疼痛発作症 / 難病 / ＳＣＮ11Ａ / チャネロパチー |
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| Outline of Final Research Achievements |
We reported the two novel mutations p.R222H/S in SCN11A, which the cause of familial episodic pain (FEP) syndrome (Okuda et al., Plos one 2016).
We recruited an additional 42 new unrelated Japanese FEP families, between 2016 and 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, p.R225C and p.V1184A, additionally two novel missense variants of SCN11A p.F814C and p.F1146S in independent families. SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C and p.F1125S, orthologues of the human p.F814C and p.F1146S, respectively. Consequentially, we confirm higher level of excitability in the F802C or F1125S mice than in WT as R222S mouse. These results indicate that these novel mutations are gain of function mutations. These results published in 2018.
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| Free Research Field |
生理学
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| Academic Significance and Societal Importance of the Research Achievements |
疼痛発症のメカニズムおよびその診断や治療法は未だ確立されていない中、我々は小児における発作性四肢疼痛の原因遺伝子を確定し、新たな疾患概念として「小児四肢疼痛発作症」と命名、初めて遺伝子検査を可能にした。さらに、本疾患は日本全国に分布していることを解明し、これまで見過ごされてきた本疾患患者が未だ潜在的に多く存在している可能性を示唆した。本課題で同定したSCN11A変異はこれまで海外症例のみの報告であり、新たな疼痛機序解明の糸口となりうると考える。今後、引き続き全国的な症例収集、遺伝子変異の同定、客観的診断基準の確立を行うことによって、本疾患の社会的認知と治療体制整備への寄与が可能になると考える。
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