BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

Nat Med. 2018 Nov;24(11):1662-1668. doi: 10.1038/s41591-018-0172-x. Epub 2018 Sep 17.


Pediatric brain tumors are highly associated with epileptic seizures1. 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 epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAFV600E 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 BRAFV600E-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 BRAFV600E 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / physiopathology
  • Brain Neoplasms / complications
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / physiopathology
  • Child
  • Disease Models, Animal
  • Ganglioglioma / complications
  • Ganglioglioma / diagnostic imaging
  • Ganglioglioma / genetics*
  • Ganglioglioma / physiopathology
  • Humans
  • Mice
  • Mutation
  • Pediatrics
  • Proto-Oncogene Proteins B-raf / genetics*
  • Repressor Proteins / genetics*
  • Seizures / complications
  • Seizures / diagnostic imaging
  • Seizures / genetics*
  • Seizures / physiopathology


  • RE1-silencing transcription factor
  • Repressor Proteins
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf