Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia

Autor: Sarah Weckhuysen, Margitta Seeck, Bart Dermaut, Alfred Meurs, Michel Baulac, Stéphanie Baulac, Pierre de la Grange, Francine Chassoux, Elise Marsan, Fabienne Picard, Eric LeGuern, Cécile Marchal, Pierre Thomas, Isabelle An-Gourfinkel, Mélanie Morin-Brureau, Christine Kallay Zetchi, Virginie Lambrecq, Martine Fohlen
Přispěvatelé: HAL-UPMC, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'épileptologie [CHU de Bordeaux], CHU Bordeaux [Bordeaux], Service de Neurochirurgie Pediatrique, Fondation Ophtalmologique Rotschild, Department of Neurology [Genève], Hôpitaux Universitaires de Genève (HUG), University of Geneva Medical School, Center for Medical Genetics [Ghent], Ghent University Hospital, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Dpt of Neurology [Gent], Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Sainte Anne, Centre hospitalier Sainte Anne, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroprotection & Neuromodulation
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
DEPDC5
DNA Mutational Analysis
mTORC1
Gene mutation
Cohort Studies
Epilepsy
0302 clinical medicine
genetics
Child
Medicine(all)
Aged
80 and over
TOR Serine-Threonine Kinases
GTPase-Activating Proteins
Middle Aged
NPRL3
Magnetic Resonance Imaging
3. Good health
Malformations of Cortical Development
mTOR pathway
Neurology
SUDEP 22 text pages
Child
Preschool
5 figures
1 table
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Adult
Biology
03 medical and health sciences
Young Adult
familial focal epilepsies
NPRL2
medicine
Humans
Genetic Predisposition to Disease
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
PI3K/AKT/mTOR pathway
35 references
Aged
Family Health
Tumor Suppressor Proteins
Infant
Newborn
fical cortical dysplasia
Infant
GATOR2 complex
Cortical dysplasia
3249 words (including summary)
medicine.disease
complex genes
ddc:616.8
Repressor Proteins
030104 developmental biology
Positron-Emission Tomography
Involvement of Gator
Mutation
Cancer research
Neurology (clinical)
Epilepsies
Partial
Human medicine
Neuroscience
030217 neurology & neurosurgery
Zdroj: Epilepsia
Epilepsia, 2016, 57 (6), pp.994-1003 ⟨10.1111/epi.13391⟩
Epilepsia, Wiley, 2016, 57 (6), pp.994-1003 ⟨10.1111/epi.13391⟩
Epilepsia, Vol. 57, No 6 (2016) pp. 994-1003
ISSN: 0013-9580
Popis: International audience; ObjectiveThe discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum.MethodsWe performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants.ResultsWe identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP).SignificanceGATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.
Databáze: OpenAIRE
Externí odkaz: