BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

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dc.contributor.authorKoh, Hyun Yongko
dc.contributor.authorKim, Se Hoonko
dc.contributor.authorJang, Jaesonko
dc.contributor.authorKim, Hyunggukko
dc.contributor.authorHan, Sungwookko
dc.contributor.authorLim, Jae Seokko
dc.contributor.authorSon, Geurimko
dc.contributor.authorChoi, Junjeongko
dc.contributor.authorPark, Byung Oukko
dc.contributor.authorHeo, Won Doko
dc.contributor.authorHan, Jinjuko
dc.contributor.authorLee, Hyunjoo Jennyko
dc.contributor.authorLee, Daeyoupko
dc.contributor.authorKang, Hoon-Chulko
dc.contributor.authorShong, Minhoko
dc.contributor.authorPaik, Se-Bumko
dc.contributor.authorKim, Dong Seokko
dc.contributor.authorLee, Jeong Hoko
dc.date.accessioned2018-11-22T07:06:55Z-
dc.date.available2018-11-22T07:06:55Z-
dc.date.created2018-11-19-
dc.date.created2018-11-19-
dc.date.created2018-11-19-
dc.date.issued2018-11-
dc.identifier.citationNATURE MEDICINE, v.24, no.11, pp.1662 - 1668-
dc.identifier.issn1078-8956-
dc.identifier.urihttp://hdl.handle.net/10203/246885-
dc.description.abstractPediatric brain tumors are highly associated with epileptic seizures(1). However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy(2). To do so, we developed a mouse model harboring the BRAF(V600E) somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAF(V600E) mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAF(V600E)-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAF(V600E) inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.-
dc.languageEnglish-
dc.publisherNATURE PUBLISHING GROUP-
dc.titleBRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors-
dc.typeArticle-
dc.identifier.wosid000449404200016-
dc.identifier.scopusid2-s2.0-85053489720-
dc.type.rimsART-
dc.citation.volume24-
dc.citation.issue11-
dc.citation.beginningpage1662-
dc.citation.endingpage1668-
dc.citation.publicationnameNATURE MEDICINE-
dc.identifier.doi10.1038/s41591-018-0172-x-
dc.contributor.localauthorHeo, Won Do-
dc.contributor.localauthorHan, Jinju-
dc.contributor.localauthorLee, Hyunjoo Jenny-
dc.contributor.localauthorLee, Daeyoup-
dc.contributor.localauthorPaik, Se-Bum-
dc.contributor.localauthorLee, Jeong Ho-
dc.contributor.nonIdAuthorKim, Se Hoon-
dc.contributor.nonIdAuthorKim, Hyungguk-
dc.contributor.nonIdAuthorChoi, Junjeong-
dc.contributor.nonIdAuthorPark, Byung Ouk-
dc.contributor.nonIdAuthorKang, Hoon-Chul-
dc.contributor.nonIdAuthorShong, Minho-
dc.contributor.nonIdAuthorKim, Dong Seok-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusFOCAL CORTICAL DYSPLASIA-
dc.subject.keywordPlusINTELLECTUAL DISABILITY-
dc.subject.keywordPlusEPILEPSY-
dc.subject.keywordPlusEXPRESSION-
dc.subject.keywordPlusMECHANISMS-
dc.subject.keywordPlusRECEPTOR-
dc.subject.keywordPlusNETWORKS-
dc.subject.keywordPlusGENE-
dc.subject.keywordPlusGANGLIOGLIOMAS-
dc.subject.keywordPlusCLASSIFICATION-
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