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Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy


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.

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Figure 1: Deep sequencing reveals brain somatic mutations in MTOR from FCDII subjects.
Figure 2: Identified mutations lead to hyperactivation of mTOR kinase protein.
Figure 3: The identified mutation induces spontaneous seizures and cytomegalic neurons rescued by rapamycin treatment.

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We thank E.J. Kim, J. Kim and S. Kim at KAIST for stimulating discussion and critical reading of the manuscript, S.M. Park at KAIST for coordinating clinical information, M.H. Kim at KAIST for analyzing behavioral seizures, J.S. Lee at Yonsei University Health System (YUHS) for providing clinical information, and K.L. Guan at the University of California–San Diego for kindly providing Flag-mTOR construct. This work was supported by a grant of the Korean Health Technology Research and Development (R&D) Project, Ministry of Health & Welfare, Republic of Korea (A121070 to J.H. Lee; HI13C0208 to J.H. Lee and D.S. Kim), the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, Information and Communication Technology (ICT) & Future Planning (2013M3C7A1056564 to J.H. Lee), and the KAIST Future Systems Healthcare Project from the Ministry of Science, ICT and Future Planning (to H.M. Kim, D. Kim and J.H. Lee).

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Authors and Affiliations



J.S.L. organized the project, and J.S.L. and W.K. performed genetic studies. S.H.K. performed pathological studies. H.R. adjusted the condition of deep WES. J.S.L. performed bioinformatics analysis with S.K. and J.K. J.S.L. and W.K. performed immunostaining and in vivo studies. W.K. and Y.-W.C. performed in vitro studies. H.M.K. modeled the three-dimensional structure of mTOR. D.K., A.H.P. and J.S. Lim performed video-EEG recording and analysis of seizures. D.-S.K. and H.-C.K. performed surgeries, collected patient samples and managed patient information and tissues samples with S.H.K., J.A.K., S.-G.K., E.K.P. and H.D.K. D.-S.K. and J.H.L. led the project and oversaw the manuscript preparation.

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Correspondence to Dong-Seok Kim or Jeong Ho Lee.

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The authors declare no competing financial interests.

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Supplementary Tables 1–5 and Supplementary Figures 1–9 (PDF 6971 kb)

Video-EEG monitoring of the spontaneous seizure in mTORp

Leu2427Pro electroporated mouse. (MP4 2129 kb)

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Lim, J., Kim, Wi., Kang, HC. et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 21, 395–400 (2015).

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