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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50 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

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W. I., Kim, J., Park, S. M., Lee, J., Oh, J. H., Kim, H. D., Park, C. H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H. C., Kim, H. H., & Lee, J. H. (2017). Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. American Journal of Human Genetics, 100(3), 454-472.