Jae Seok Lim1,10, Woo-il Kim1,10, Hoon-Chul Kang2,3,10, Se Hoon Kim4, Ah Hyung Park5, Eun Kyung Park3,6, Young-Wook Cho7, Sangwoo Kim8, Ho Min Kim1, Jeong A Kim2,3, Junho Kim8, Hwanseok Rhee9, Seok-Gu Kang3,6, Heung Dong Kim2,3, Daesoo Kim5, Dong-Seok Kim3,6,11 & Jeong Ho Lee1,11
1Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea. 2Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children’s Hospital, Seoul, Korea. 3Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Korea. 4Department of Pathology, Brain Korea 21 project for medical science, Yonsei University College of Medicine, Seoul, Korea. 5Department of Biological Sciences, KAIST, Daejeon, Korea. 6Department of Neurosurgery, Pediatric Epilepsy Clinics, Brain Korea 21 project for medical science, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea. 7Korea Basic Science Institute, Chuncheon Center, Chuncheon-si, Gangwon-do, Korea. 8Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. 9Macrogen Bioinformatics Center, Macrogen, Gasan-dong, Geumcheon-gu, Seoul, Korea. 10These authors contributed equally to this work. 11These authors jointly directed this work.
Correspondence to: Jeong Ho Lee or Dong-Seok Kim
Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy1, 2. It has been hypothesized that FCD is caused by somatic mutations in affected regions3, 4. 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.