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.
|Number of pages||17|
|Journal||Journal of Clinical Investigation|
|Publication status||Published - 2019 Oct 1|
Bibliographical noteFunding Information:
This work was supported by grants from the Suh Kyungbae Foundation (to JHL); the Korean Health Technology R&D Project; the National Research Foundation of Korea (NRF), funded by the Korean government, Ministry of Science and ICT (2019R1A3B2066619, to JHL), and the Ministry of Health and Welfare, Republic of Korea (H15C3143 and H16C0415 to JHL). JKK is a Cheong-Am Science Fellow supported by POSCO Cheong-Am Foundation. Some tissue, biological specimens, and data used in this research were obtained from Autism Brain-Net, which is sponsored by the Simons Foundation and Autism Speaks. The authors also acknowledge the Autism Tissue Program that was the predecessor to Autism BrainNet.
© 2019, American Society for Clinical Investigation.
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