BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

Nature Medicine
Hyun Yong KohJeong Ho Lee

Abstract

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 stu...Continue Reading

References

Aug 25, 2001·Epilepsia·E Perucca
May 7, 2002·Nature Genetics·Patrick CossetteGuy A Rouleau
Jun 7, 2002·Current Opinion in Neurobiology·Claire M Sauvageot, Charles D Stiles
Jul 2, 2002·Journal of Neurophysiology·H Nadeau, H A Lester
Jul 20, 2002·Journal of Neuropathology and Experimental Neurology·Ingmar Blümcke, Otmar D Wiestler
Apr 17, 2007·Lancet Neurology·Melanie S M van BreemenCharles J Vecht
Apr 18, 2007·Epilepsia·Uzma SamadaniPeter B Crino
May 24, 2008·Clinical Neurology and Neurosurgery·Young Seok ParkJoong-Uhn Choi
Sep 17, 2008·Oncogene·T L Yuan, L C Cantley
Apr 7, 2009·Cancer Cell·Nathalie DhomenRichard Marais
Jan 8, 2011·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Molly HardtFuyuhiko Tamanoi
Mar 19, 2011·Brain : a Journal of Neurology·Emanuele ZuroloEleonora Aronica
Mar 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Kyung-Min NohR Suzanne Zukin
Mar 27, 2012·Nature Neuroscience·Sébastien RoyerGyörgy Buzsáki
Mar 29, 2012·The Journal of Pharmacology and Experimental Therapeutics·Rajendar K MittapalliWilliam F Elmquist
Apr 14, 2012·Brain Pathology·Maria ThomEleonora Aronica
May 31, 2012·Epilepsia·UNKNOWN Epi4K Consortium
Sep 1, 2012·Nature Protocols·Gerard M J BeaudoinJyothi Arikkath
Apr 16, 2013·Progress in Neurobiology·Bridgette D SempleLinda J Noble-Haeusslein
Apr 19, 2013·Nature Reviews. Neuroscience·Ethan M Goldberg, Douglas A Coulter
Nov 26, 2013·Annals of Neurology·Johannes R LemkeSarah Weckhuysen
Dec 18, 2013·Epilepsia·Melissa Kerkhof, Charles J Vecht
Apr 22, 2014·Nature Genetics·Caroline NavaChristel Depienne
Aug 16, 2014·American Journal of Medical Genetics. Part a·Siddharth SrivastavaAli Fatemi
Sep 4, 2015·Nature Communications·Tommy StödbergManju A Kurian
Nov 20, 2016·Nature Reviews. Neurology·Ingmar BlümckeMaria Thom
Feb 22, 2017·American Journal of Human Genetics·Jae Seok LimJeong Ho Lee

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Citations

Oct 31, 2018·Nature Medicine·Jean M Mulcahy Levy, Martin McMahon
Feb 15, 2019·Current Opinion in Neurology·Philip H Iffland, Peter B Crino
Jun 12, 2019·Cancers·Felix Behling, Jens Schittenhelm
Oct 20, 2018·Nature Reviews. Drug Discovery·Megan Cully
Oct 3, 2019·Current Opinion in Neurology·Marta Penas-PradoMark R Gilbert
Jan 23, 2020·Epilepsy Currents·Bernard S ChangUNKNOWN NINDS/AES Epilepsy Research Benchmark Stewards Committee
Jan 23, 2020·Cancer·L Nicolas Gonzalez Castro, Tracey A Milligan
Aug 20, 2020·Acta Neuropathologica Communications·Kensuke TateishiTetsuya Yamamoto
Sep 28, 2018·Nature Reviews. Neurology·Charlotte Ridler
May 16, 2019·Journal of Korean Neurosurgical Society·Ji Hoon Phi, Seung-Ki Kim
Aug 5, 2019·Acta Neuropathologica·Nam Suk SimJeong Ho Lee
Mar 11, 2020·Acta Neuropathologica Communications·Rutger Juriaan Slegers, Ingmar Blumcke
Jul 28, 2020·Pharmaceuticals·Angel Escamilla-RamírezCristina Trejo-Solís
Jul 1, 2020·Current Neurology and Neuroscience Reports·Jigisha P ThakkarRimas V Lukas
Oct 12, 2020·Journal of Human Genetics·Yena LeeBeom Hee Lee
Apr 2, 2021·Journal of Molecular Neuroscience : MN·Hang XingPeter David Koch
Apr 20, 2021·Biological Psychiatry·Myeong-Heui KimJeong Ho Lee
May 5, 2021·Neuropathology and Applied Neurobiology·Anatoly KorotkovEleonora Aronica
Jun 29, 2021·Annals of Neurology·Hyun Yong KohJeong Ho Lee
May 13, 2021·Annual Review of Genomics and Human Genetics·Michael B MillerChristopher A Walsh
Jan 29, 2020·Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology·Ran ZhangTiejun Li

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Methods Mentioned

BETA
laser capture microdissection
immunoprecipitation
amplicon sequencing
PCR
Protein Assay
dissection
chip
PCRs
transfection

Software Mentioned

ClueGO
EEGLAB
GraphPad
Ingenuity
ImageJ
SnpEFF
GATK
Ingenuity Pathway Analysis
MATLAB
Mobius

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