title: Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations.
abstract: We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.forename: Brigid M
authors.initials: BM
authors.lastname: Regan
authors.forename: Simone
authors.initials: S
authors.lastname: Mandelstam
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Crompton
authors.forename: Bree L
authors.initials: BL
authors.lastname: Hodgson
authors.forename: Laura
authors.initials: L
authors.lastname: Licchetta
authors.forename: Federica
authors.initials: F
authors.lastname: Provini
authors.forename: Francesca
authors.initials: F
authors.lastname: Bisulli
authors.forename: Lata
authors.initials: L
authors.lastname: Vadlamudi
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Alan
authors.initials: A
authors.lastname: Connelly
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ricos
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
mesh_terms: D000328:Adult; D001921:Brain / Q000002:abnormalities*; D002648:Child; D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D055815:Young Adult
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D012097:Repressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases