Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Jae Seok Lim, Ramu Gopalappa, Se Hoon Kim, Suresh Ramakrishna, Minji Lee, Woo il Kim, Junho Kim, Sang Min Park, Junehawk Lee, Jung Hwa Oh, Heung Dong Kim, Chang Hwan Park, Joon Soo Lee, Sangwoo Kim, Dong Seok Kim, Jung Min Han, Hoon Chul Kang, Hyongbum (Henry) Kim, Jeong Ho Lee

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135 Citations (Scopus)


Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%–25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×–20,012×) of five important mTOR pathway genes—PIK3CA, PIK3R2, AKT3, TSC1, and TSC2—by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

Original languageEnglish
Pages (from-to)454-472
Number of pages19
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - 2017 Mar 2

Bibliographical note

Funding Information:
We thank Dr. Sun Min Park at the Korea Advanced Institute of Science and Technology (KAIST) for coordinating clinical information. This work was supported by the Korean Health Technology R&D Project of the Korean Ministry of Health & Welfare (grants H15C3143 and H16C0415 to J.H.L., HI14C1588 and HI15C1601 to H.C.K., and HI14C2019 to H.K.); Citizens United for Research in Epilepsy (J.H.L.); the Brain Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (grants 2013M3C7A1056564 to J.H.L. and 2015R1A2A1A15052668 to H.K.); and the KAIST Future Systems Healthcare Project from the Ministry of Science, ICT, and Future Planning (J.H.L.).

Publisher Copyright:
© 2017 American Society of Human Genetics

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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