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J Clin Invest. 2019 Oct 1;129(10):4207-4223. doi: 10.1172/JCI127032.

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

Kim JK1, Cho J2,3, Kim SH4, Kang HC5, Kim DS6,7, Kim VN3,8, Lee JH1,9.

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Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.


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.


Epilepsy; Genetic variation; Neuroscience; Therapeutics; Translation

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