title: Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3.
abstract: Mutations in NPRL3, one of three genes that encode proteins of the mTORC1-regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel- or DEPDC5-associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms.
authors.affiliation: Pediatrics Hospital, Klinikum Oldenburg, Oldenburg, Germany.
authors.forename: Georg-Christoph
authors.initials: GC
authors.lastname: Korenke
authors.affiliation: Institute of Human Genetics, Ludwig-Maximilians-University Hospital, Munich, Germany.
authors.forename: Marlene
authors.initials: M
authors.lastname: Eggert
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Institute of Human Genetics, Ludwig-Maximilians-University Hospital, Munich, Germany.
authors.forename: Ortrud K
authors.initials: OK
authors.lastname: Steinlein
mesh_terms: D002648:Child; D002675:Child, Preschool; D017034:Epilepsy, Frontal Lobe / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree
chemical_list: D020690:GTPase-Activating Proteins; C543618:NPRL3 protein, human
keywords: GATOR1; NPRL3; Nocturnal frontal lobe epilepsy; Oldenburg; mTORC1 Pathway