title: Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.
abstract: The 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.
  
  
  
  We 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.
  
  
  
  We 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).
  
  
  
  GATOR1 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.
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Centre de référence épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Marsan
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Centre de référence épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lambrecq
authors.affiliation: CHU de Bordeaux, service d'épileptologie, Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Marchal
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Morin-Brureau
authors.affiliation: INSERM, U1127, ICM, Paris, France.|Centre de référence épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: An-Gourfinkel
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Centre de référence épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Baulac
authors.affiliation: Department of Pediatric Neurosurgery, Rothschild Foundation, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Fohlen
authors.affiliation: Department of Neurology, University Hospitals (HUG) and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Kallay Zetchi
authors.affiliation: Department of Neurology, University Hospitals (HUG) and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Margitta
authors.initials: M
authors.lastname: Seeck
authors.affiliation: Genosplice Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Gent, Belgium.|Inserm U1167, Institut Pasteur de Lille, Université de Lille, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.affiliation: Department of Neurology, Ghent University Hospital, Gent, Belgium.
authors.forename: Alfred
authors.initials: A
authors.lastname: Meurs
authors.affiliation: Service de Neurologie, Hôpital Pasteur, Nice, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Centre hospitalier Sainte-Anne, Université Paris Descartes, Paris, France.
authors.forename: Francine
authors.initials: F
authors.lastname: Chassoux
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Département de Génétique et de Cytogénétique, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.affiliation: Department of Neurology, University Hospitals (HUG) and Medical School of Geneva, Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Picard
authors.affiliation: INSERM, U1127, ICM, Paris, France.|CNRS, UMR 7225, ICM, Paris, France.|Sorbonne Universités, UMR S 1127, UPMC Univ Paris 06, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Département de Génétique et de Cytogénétique, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004828:Epilepsies, Partial / Q000000981:diagnostic imaging / Q000235:genetics*; D005192:Family Health; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000000981:diagnostic imaging / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D049268:Positron-Emission Tomography; D012097:Repressor Proteins / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; C492816:NPRL2 protein, human; C543618:NPRL3 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases
keywords: DEPDC5; Genetics; NPRL2; NPRL3; SUDEP; mTOR