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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 Therapeutics

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 1

Ribosome profiling in the intractable epilepsy mouse models with brain somatic mutations in MTOR reveals mTOR target genes contributing to FMCD.

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Ribosome profiling in the intractable epilepsy mouse models with brain s...
(A) Schematic diagram depicts the enrichment of low-level mutation-carrying neurons by FACS from FMCD mice using GFP reporter. Scale bars: 200 μm. (B) Venn diagrams show the number of genes identified from Ribo-Seq and RNA-Seq analysis of mTOR WT (WT), mTOR p.Cys1483Tyr (p.C1483Y), and mTOR p.Leu2427Pro (p.L2427P) mice. Distribution of TE changes in p.C1483Y or p.L2427P mice relative to WT mice. Upregulated mRNAs (Z score ≥ 1.2) are labeled as red in p.C1483Y (left) and p.L2427P (right) mice. See also Supplemental Tables 2 and 3. (C) Functional enrichment analysis of mTOR activation–sensitive genes in FMCD. Each circle represents a functional cluster. Color intensity indicates the statistical significance of functional enrichment as determined by average P value. The size of the circle corresponds to the number of genes, whereas the coordinates indicate average fold change values of p.C1483Y versus WT (x axis) and p.L2427P versus WT (y axis). Numbers of genes are given in parentheses. See also Supplemental Figure 3H.
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