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Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy
Jang Keun Kim, … , V. Narry Kim, Jeong Ho Lee
Jang Keun Kim, … , V. Narry Kim, Jeong Ho Lee
Published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4207-4223. https://doi.org/10.1172/JCI127032.
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Research Article Neuroscience

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

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Abstract

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.

Authors

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

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Figure 4

mTOR activation–sensitive genes confer mTOR-responsive 5′-UTR motifs.

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mTOR activation–sensitive genes confer mTOR-responsive 5′-UTR motifs.
(A...
(A) 5′-UTR–mediated translation of target mRNAs (Adk-S, Adk-L, Creb1, and IRSp53) and control mRNAs (Actb and Gapdh) by 5′-UTR luciferase reporter assay in HEK293T cells transfected with mTOR WT (WT) and mTOR p.C1483Y or p.L2427P. Pro denotes promoter. Actb denotes β-actin gene. pGL3 denotes the test vector lacking a 5′-UTR. Results are normalized to 5′-UTR reporter activity in transfected mTOR WT cells. n = 7 in each case. Mean ± SD. (B) Consensus sequence and enrichment values (e value) of the U-rich, guanine quartet (GGC)4, A-rich, and CERT motifs identified in mTOR activation–sensitive genes in FMCD mice and C1483Y cells by MEME analysis. Diagram illustrating the frequencies of mTOR activation–sensitive genes in FMCD mice and C1483Y cells containing U-rich, guanine quartet (GGC)4, A-rich, and CERT motifs. Several motifs in the same genes were counted independently. See also Supplemental Tables 11 and 13. (C) Location of 5′-UTR motifs in Adk-S, IRSp53, and Creb1 is indicated. Effect of deletion mutations in 5′-UTR motif domains in Adk-S, IRSp53, and Creb1 on 5′-UTR luciferase reporter activity in mTOR-activated p.C1483Y or p.L2427P cells relative to WT-transfected HEK293T cells. Pro denotes promoter. n = 7 in each case. Mean ± SD. See also Supplemental Table 14. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA with Bonferroni’s post hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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