Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy

Jang Keun Kim, Jun Cho, Se Hoon Kim, Hoon Chul Kang, Dong Seok Kim, V. Narry Kim, Jeong Ho Lee

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


Brain somatic mutations confer genomic diversity in the human brain and cause neurodevelopmental disorders. Recently, brain somatic activating mutations in MTOR have been identified as a major etiology of intractable epilepsy in patients with cortical malformations. However, the molecular genetic mechanism of how brain somatic mutations in MTOR cause intractable epilepsy has remained elusive. In this study, translational profiling of intractable epilepsy mouse models with brain somatic mutations and genome-edited cells revealed a novel translational dysregulation mechanism and mTOR activation-sensitive targets mediated by human MTOR mutations that lead to intractable epilepsy with cortical malformation. These mTOR targets were found to be regulated by novel mTOR-responsive 5'-UTR motifs, distinct from known mTOR inhibition-sensitive targets regulated by 5 terminal oligopyrimidine motifs. Novel mTOR target genes were validated in patient brain tissues, and the mTOR downstream effector eIF4E was identified as a new therapeutic target in intractable epilepsy via pharmacological or genetic inhibition. We show that metformin, an FDA-approved eIF4E inhibitor, suppresses intractable epilepsy. Altogether, the present study describes translational dysregulation resulting from brain somatic mutations in MTOR, as well as the pathogenesis and potential therapeutic targets of intractable epilepsy.

Original languageEnglish
Pages (from-to)4207-4223
Number of pages17
JournalJournal of Clinical Investigation
Issue number10
Publication statusPublished - 2019 Oct 1

Bibliographical note

Publisher Copyright:
© 2019, American Society for Clinical Investigation.

All Science Journal Classification (ASJC) codes

  • General Medicine


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