Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

Primary accessions

Sequence Read Archive


  1. Bast, T., Ramantani, G., Seitz, A. & Rating, D. Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol. Scand. 113, 72–81 (2006).

    Article  CAS  Google Scholar 

  2. Taylor, D.C., Falconer, M.A., Bruton, C.J. & Corsellis, J.A. Focal dysplasia of the cerebral cortex in epilepsy. J. Neurol. Neurosurg. Psychiatry 34, 369–387 (1971).

    Article  CAS  Google Scholar 

  3. Crino, P.B. Focal brain malformations: seizures, signaling, sequencing. Epilepsia 50 (suppl. 9), 3–8 (2009).

    Article  CAS  Google Scholar 

  4. Poduri, A., Evrony, G.D., Cai, X. & Walsh, C.A. Somatic mutation, genomic variation, and neurological disease. Science 341, 1237758 (2013).

    Article  Google Scholar 

  5. Krsek, P. et al. Different features of histopathological subtypes of pediatric focal cortical dysplasia. Ann. Neurol. 63, 758–769 (2008).

    Article  Google Scholar 

  6. Fauser, S. et al. Focal cortical dysplasias: surgical outcome in 67 patients in relation to histological subtypes and dual pathology. Brain 127, 2406–2418 (2004).

    Article  Google Scholar 

  7. Blümcke, I. et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52, 158–174 (2011).

    Article  Google Scholar 

  8. Fauser, S. et al. Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 129, 1907–1916 (2006).

    Article  Google Scholar 

  9. Chen, J. et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann. Neurol. 72, 881–892 (2012).

    Article  CAS  Google Scholar 

  10. Sisodiya, S.M., Fauser, S., Cross, J.H. & Thom, M. Focal cortical dysplasia type II: biological features and clinical perspectives. Lancet Neurol. 8, 830–843 (2009).

    Article  Google Scholar 

  11. Colombo, N. et al. Focal cortical dysplasia type IIa and IIb: MRI aspects in 118 cases proven by histopathology. Neuroradiology 54, 1065–1077 (2012).

    Article  Google Scholar 

  12. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  Google Scholar 

  13. Kim, S. et al. Virmid: accurate detection of somatic mutations with sample impurity inference. Genome Biol. 14, R90 (2013).

    Article  Google Scholar 

  14. Robasky, K., Lewis, N.E. & Church, G.M. The role of replicates for error mitigation in next-generation sequencing. Nat. Rev. Genet. 15, 56–62 (2014).

    Article  CAS  Google Scholar 

  15. Shirley, M.D. et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med. 368, 1971–1979 (2013).

    Article  CAS  Google Scholar 

  16. Williams, C. et al. A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am. J. Pathol. 155, 1467–1471 (1999).

    Article  CAS  Google Scholar 

  17. Grabiner, B.C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563 (2014).

    Article  CAS  Google Scholar 

  18. Yang, H. et al. mTOR kinase structure, mechanism and regulation. Nature 497, 217–223 (2013).

    Article  CAS  Google Scholar 

  19. Urano, J. et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc. Natl. Acad. Sci. USA 104, 3514–3519 (2007).

    Article  CAS  Google Scholar 

  20. Crino, P.B. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol. Med. 17, 734–742 (2011).

    Article  CAS  Google Scholar 

  21. Navarro-Quiroga, I., Chittajallu, R., Gallo, V. & Haydar, T.F. Long-term, selective gene expression in developing and adult hippocampal pyramidal neurons using focal in utero electroporation. J. Neurosci. 27, 5007–5011 (2007).

    Article  CAS  Google Scholar 

  22. Rivière, J.B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012).

    Article  Google Scholar 

  23. Poduri, A. et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74, 41–48 (2012).

    Article  CAS  Google Scholar 

  24. Lee, J.H. et al. De novo somatic mutations in components of the PI3K–AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44, 941–945 (2012).

    Article  CAS  Google Scholar 

  25. Reumers, J. et al. Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing. Nat. Biotechnol. 30, 61–68 (2012).

    Article  CAS  Google Scholar 

  26. Krueger, D.A. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363, 1801–1811 (2010).

    Article  CAS  Google Scholar 

  27. Krueger, D.A. et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann. Neurol. 74, 679–687 (2013).

    Article  CAS  Google Scholar 

  28. Aronica, E., Becker, A.J. & Spreafico, R. Malformations of cortical development. Brain Pathol. 22, 380–401 (2012).

    Article  Google Scholar 

  29. Crino, P.B., Nathanson, K.L. & Henske, E.P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345–1356 (2006).

    Article  CAS  Google Scholar 

  30. Feliciano, D.M., Su, T., Lopez, J., Platel, J.C. & Bordey, A. Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J. Clin. Invest. 121, 1596–1607 (2011).

    Article  CAS  Google Scholar 

  31. Baybis, M. et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol. 56, 478–487 (2004).

    Article  CAS  Google Scholar 

  32. Miyata, H., Chiang, A.C. & Vinters, H.V. Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann. Neurol. 56, 510–519 (2004).

    Article  CAS  Google Scholar 

  33. Liu, J. et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun 2, 71 (2014).

    Article  Google Scholar 

  34. Yasin, S.A. et al. mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathol. 126, 207–218 (2013).

    Article  CAS  Google Scholar 

  35. Becker, A.J. et al. Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann. Neurol. 52, 29–37 (2002).

    Article  CAS  Google Scholar 

  36. Scheffer, I.E. et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann. Neurol. 75, 782–787 (2014).

    Article  CAS  Google Scholar 

  37. Kim, Y.H. et al. Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery. Epilepsia 52, 722–727 (2011).

    Article  Google Scholar 

  38. Zeng, L.H., Xu, L., Gutmann, D.H. & Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444–453 (2008).

    Article  CAS  Google Scholar 

Download references


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).

Author information

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.

Corresponding authors

Correspondence to Dong-Seok Kim or Jeong Ho Lee.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research