BRAF V600E mutation in neocortical posterior temporal epileptogenic gangliogliomas

Martinoni, Matteo; Marucci, Gianluca; Biase, Dario de; Rubboli, Guido; Volpi, L.; Riguzzi, P.; Marliani, Federica; Toni, Francesco; Naldi, Ilaria; Bisulli, Francesca; Tinuper, Paolo; Michelucci, Roberto; Baruzzi, Agostino; Tallini, Giovanni; Giulioni, Marco

doi:10.1016/j.jocn.2015.02.016

Cited by 16 publications

(18 citation statements)

References 28 publications

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“…However, we have not shown that cells from agminated melanocytic nevi are affected with the same mutation as epidermal nevus cells, due to ethical limitations to tissue sampling. Regarding the neurologic phenotype, BRAF p.Val600Glu somatic mutations have previously been found in neocortical posterior temporal epilepsyassociated gangliogliomas or low-grade cerebral tumors, possibly with FCD type IIa (Martinoni et al, 2015;Marucci et al, 2014). The presence of the BRAF p.Lys601Asn mutation was not looked for in brain tissue, due to the absence of cerebral biopsy.…”

Section: To the Editormentioning

confidence: 99%

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia

Kuentz¹,

Mignot²,

St‐Onge³

et al. 2016

Journal of Investigative Dermatology

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Section: To the Editormentioning

confidence: 99%

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia

Kuentz¹,

Mignot²,

St‐Onge³

et al. 2016

Journal of Investigative Dermatology

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“…Differential gene expression was estimated with DESeq2 1.18.1 (RRID:SCR_015687) 97 in R 3.4.4 (RRID:SCR_001905) 98 using R Studio GUI 99 and FDR corrected pvalues (q values) of 0.05 were considered significant 100 . The results of differentially expressed genes were further analyzed for functional enrichment with DAVID 6.8 101,102 (https://david.ncifcrf.gov/home.jsp) Gene Analytics web-service (geneanalytics.genecards.org) 103 was used to analyze differentially expressed genes. Pseudorandom mouse gene list was generated in molecular biology online apps web tool (http://molbiotools.com/randomgenesetgenerator.html) using Mersenne Twister 104 pseudorandom number generator algorithm (from personal communication with Vladimír Čermák, the site developer).…”

Section: Rnaseq Gene Ontology Analysis and Gene Analyticsmentioning

confidence: 99%

BRAFV600E Expression in Mouse Neuroglial Progenitors Increase Neuronal Excitability, Cause Appearance of Balloon-like cells, Neuronal Mislocalization, and Inflammatory Immune response

Goz

2019

Preprint

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BACKGROUND: Frequent de-novo somatic mutations in major components (PI3KCA, AKT3, TSC1, TSC2, mTOR, BRAF) of molecular pathways crucial for cell differentiation, proliferation, growth and migration (mTOR, MAPK) has been previously implicated in malformations of cortical development (MCDs) and low-grade neuroepithelial tumors (LNETs) [1][2][3][4][5][6][7] . LNETs are the most frequent tumors found in patients undergoing resective surgery for refractory epilepsy treatment. BRAFV600E is found in up to 70% of LNETs. Previous studies suggest a causal relationship between those de-novo somatic mutations in mTOR, MAPK pathways and seizures occurrence, even without presence of malformation or a tumor 2,3,[8][9][10][11][12][13] In the recently developed mouse models of MCD and GG genetic alterations in MTOR and MAPK components in a small population of cortical cells was enough to disrupt cortical structure, cell morphology and cause seizures. Moreover, administration of MTOR and MAPK specific components inhibitors was enough to decrease seizures and prevent structural malformation. 2,3,9,14,73 . However, the intrinsic electrophysiological mechanisms that may lead to seizures at the single cell level in those studies were not interrogated. This may be due to previous studies on FCD and TSC cases that showed no significant increase in intrinsic excitability of malformed components, including cytomegalic neurons, balloon cells and immature misoriented neurons 51,53,54,[74][75][76][77] .Here we hypothesized that expression of BRAFV600E mutation associated with LNETs alters gene expression in the affected cortical tissue and increase intrinsic neuronal excitability in BRAFV600E neurons, altering passive and active electrophysiological properties. To this end we used In-utero electroporation that allows to introduce genetic manipulation into radial glia progenitor population affecting a small percentage of cells (5-10%) 78, 79 . This manipulation reflects the percentage of mutated alleles found in MCDs 2,4,9,73,80,81 and in GG 14 . Gene expression was examined with RNA sequencing and intrinsic neuronal properties were examined ex-vivo in cortical slices with whole-cell patch clamp. Gene ontology analysis of the tissue-wide expression profiles showed that there was a significant increase in immune response, as well as classic complement pathway activation in BRAFV600E cortical tissue. The decreased biological protein pathways included potassium channels. BRAFV600E expressing neurons had hyperexcitable intrinsic properties most prominent of each was increased action potential firing and low current threshold required to fire action potential (rheobase). Other electrophysiological properties that contribute to hyperexcitability of those neurons include more depolarized resting membrane potential, increased input resistance, lower capacitance, more hyperpolarized action potential voltage threshold. In current-clamp experiments significant SAG and rebound excitation in BRAFV600E neurons were observed, a phenomenon associated with hy...

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“…As with FCDs, epilepsy surgery often results in seizure freedom for patients with neuroglial tumours [21][22][23][24][25][26][27]. Over the past few years, investigations have revealed possible genetic factors underlying the development of neuroglial tumours, especially that of the BRAF- [28][29][30] and PI3K-pathway [31] for gangliogliomas, and the FGFR1-pathway for DNTs [32,33]. Apart from these molecular signalling routes, distinct profiles of chromosomal copy number aberrations have also been described in neuroglial tumours [34].…”

Section: Introductionmentioning

confidence: 99%

Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours

Rácz

Müller

Schwerdt

et al. 2018

Seizure

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BRAF V600E mutation in neocortical posterior temporal epileptogenic gangliogliomas

Cited by 16 publications

References 28 publications

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia

Postzygotic BRAF p.Lys601Asn Mutation in Phacomatosis Pigmentokeratotica with Woolly Hair Nevus and Focal Cortical Dysplasia

BRAFV600E Expression in Mouse Neuroglial Progenitors Increase Neuronal Excitability, Cause Appearance of Balloon-like cells, Neuronal Mislocalization, and Inflammatory Immune response

Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours

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