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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 2

mTOR activation–sensitive genes in patients’ brain tissues with somatic mutations in MTOR.

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mTOR activation–sensitive genes in patients’ brain tissues with somatic ...
(A) Representative brain MRI from a TSC, an FCD, and an HME patient with MTOR activating mutation. Arrows highlight the affected cortical region. Representative immunofluorescence staining of translationally upregulated mTOR targets (ADK, IRSp53, and CREB1 [red]) in NeuN+ (green) cells from the patient’s brain tissues stained with DAPI (blue). Scale bars: 25 μm for ADK and CREB1 and 60 μm for IRSp53. Control 1 refers to the postmortem brain tissues of UMB5309. (B) Quantification of samples in A. ADK, IRSp53, or CREB1 positivity in NeuN+ cells from TSC, FCD, and patients with HME. Five images were quantified in each section. Mean ± SD. (C) Western blots of ADK, IRSp53, CREB1, and p-S6 in lysates from patients with FMCD and control brain specimens. Arrow indicates long isoform of ADK (ADK-L), and arrowhead indicates short isoform of ADK (ADK-S). Blotting of α-tubulin in lysates was used as a loading control. Control 1 (Con1) refers to the postmortem brain region of UMB5309, Con2 to the postmortem brain region of UMB5408, Con3 to the unaffected brain region of FCD247, Con4 to the postmortem brain region of UMB1712, and Con5 to the postmortem brain region of UMB4917. (D) Quantification of C. The level of each target protein is presented as a percentage change relative to the average of 5 control samples. n = 5 in control (Con1, Con2, Con3, Con4, and Con5), n = 4 in FCD (FCD56, FCD247, FCD254, and FCD348), n = 3 in TSC (TSC2, TSC264, and TSC357), n = 3 in HME (HME20, HME255, and HME338). Mean ± SD. *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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