title: Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.
abstract: Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.
authors: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors: Jae Seok
authors: JS
authors: Lim
authors: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors: Woo-il
authors: WI
authors: Kim
authors: 1] Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, Korea. [2] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Hoon-Chul
authors: HC
authors: Kang
authors: Department of Pathology, Brain Korea 21 project for medical science, Yonsei University College of Medicine, Seoul, Korea.
authors: Se Hoon
authors: 0000000175167372
authors: SH
authors: Kim
authors: Department of Biological Sciences, KAIST, Daejeon, Korea.
authors: Ah Hyung
authors: AH
authors: Park
authors: 1] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea. [2] Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 project for medical science, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: Eun Kyung
authors: EK
authors: Park
authors: Korea Basic Science Institute, Chuncheon Center, Chuncheon-si, Gangwon-do, Korea.
authors: Young-Wook
authors: YW
authors: Cho
authors: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Sangwoo
authors: S
authors: Kim
authors: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors: Ho Min
authors: HM
authors: Kim
authors: 1] Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, Korea. [2] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Jeong A
authors: JA
authors: Kim
authors: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Junho
authors: J
authors: Kim
authors: Macrogen Bioinformatics Center, Macrogen, Gasan-dong, Geumcheon-gu, Seoul, Korea.
authors: Hwanseok
authors: H
authors: Rhee
authors: 1] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea. [2] Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 project for medical science, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: Seok-Gu
authors: SG
authors: Kang
authors: 1] Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, Korea. [2] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Heung Dong
authors: HD
authors: Kim
authors: Department of Biological Sciences, KAIST, Daejeon, Korea.
authors: Daesoo
authors: D
authors: Kim
authors: 1] Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea. [2] Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 project for medical science, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors: Dong-Seok
authors: DS
authors: Kim
authors: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors: Jeong Ho
authors: JH
authors: Lee
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D018274:Electroporation; D004827:Epilepsy; D059472:Exome; D005091:Exons; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D004247:DNA; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus