Brain somatic mutations cause focal cortical dysplasia typeII in human and mouse. J. S. Lim1, W. I. Kim1, H. C. Kang2, S. H. Kim3, A. H. Park4, S. Kim5, D. Kim4, D. S. Kim6, J. H. Lee1 1) Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea; 2) Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Childrens Hospital, Epilepsy Research Center, Yonsei University College of Medicine, Seoul, Korea; 3) Department of Pathology, Brain Korea 21 project for medical science, Yonsei University College of Medicine, Seoul, Korea; 4) Department of Biological Sciences, KAIST, Daejeon 305-701, Korea; 5) Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea; 6) Pediatric Neurosurgery, Severance Children's Hospital, Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.

   Focal cortical dysplasia type II (FCDII) is a developmental malformation of cerebral cortex and an important cause of medically refractory epilepsy. FCDII is characterized by dysmorphic neurons interspersed with normal cells and disrupted cortical lamination in affected regions. In addition, FCD sporadically occur and show funnel-shape appearance on neuroimaging, implying that dispersed abnormal neurons are derived from progenitors at the ventricular zone. These findings suggested that FCD is caused by somatic mosaic mutations only in affected brain regions. However, no such mutations have been identified. Here, we report de novo somatic mutations of MTOR in the affected brains of FCDII patients. Deep whole exome sequencing (the median read depth of 492) of paired brain-blood DNA from 4 FCDII patients revealed brain somatic mutations in 3 patients including MTOR c.4448GA (p.Cys1483Tyr), MTOR c.7255GA (p.Glu2419Lys) and c.7280TC (p.Leu2427Pro). We also performed deep targeted sequencing (the median read depth of 135,424) of the codons encoding mTOR p.Cys1483, pGlu2419, and p.Leu2427 residues in brain tissues obtained from an additional 76 FCDII patients. In total, We identified 13 FCDII patients carrying somatic missense mutations in MTOR including mTOR p.Cys1483Tyr or Arg, pGlu2419Lys or Gly , and p.Leu2427Pro or Gln, accounting for 16.3% of all FCDII participants (13 of 80). The prevalence of the mutant allele in affected brain tissues ranged from 1.0% to 12.6%. In immunoblotting and kinase assay, the identified mutations induced the constitutive activation of mTOR kinase. Next, to determine whether the FCDII patients had the mTOR hyperactivation, we performed immunostaining in brain tissues sections obtained from FCDII patients carrying identified mutations. The results showed a marked increase in the number and size of neuronal cells positive for phosphorylated S6 in FCDII patients carrying MTOR mutations, not in non-FCD patient. Furthermore, the focal cortical expression of MTOR mutants in in utero electroporated mice was sufficient to interfere with proper neuronal migration and cause spontaneous seizures and cytomegalic neurons. Therefore, this study provides the first evidence that brain somatic mutations in MTOR cause focal cortical dysplasia.

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