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BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

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Title
BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors
Author(s)
Hyun Yong Koh; Se Hoon Kim; Jaeson Jang; Hyungguk Kim; Sungwook Han; Jae Seok Lim; Geurim Son; Junjeong Choi; Byung Ouk Park; Won Do Heo; Jinju Han; Hyunjoo Jenny Lee; Daeyoup Lee; Hoon-Chul Kang; Minho Shong; Se-Bum Paik; Dong Seok Kim; Jeong Ho Lee
Publication Date
2018-11
Journal
NATURE MEDICINE, v.24, no.11, pp.1662 - 1668
Publisher
NATURE PUBLISHING GROUP
Abstract
Pediatric 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.
URI
https://pr.ibs.re.kr/handle/8788114/6235
ISSN
1078-8956
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > Journal Papers (저널논문)
Center for Cognition and Sociality(인지 및 사회성 연구단) > Journal Papers (저널논문)
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