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.
Bibliographical noteFunding Information:
We thank K. S. Kim at the School of Medicine in Chungnam National University for breeding the Braflsl-V637E/+ mice, G. Mandel at Howard Hughes Medical Institute in Oregon Health and Science University for providing plasmid DNA of dnREST, and S. M. Park and W. K. Kim at the Korea Advanced Institute of Science and Technology (KAIST) for coordinating the clinical information. This work was supported by the Suh Kyungbae Foundation (to J.H.L.) and grants from the Citizens United for Research in Epilepsy (to J.H.L.) and the Korean Health Technology Research and Development (R&D) Project, Ministry of Health & Welfare, Republic of Korea (H15C3143 to J.H.L. and H16C0415 to D.S.K. and J.H.L.), KAIST (G04170025 to J.H.) and IBS-R002-D1 (to J.H.L).
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)