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Neurobiology
Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

https://doi.org/10.1016/j.ajpath.2017.01.015Get rights and content
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The activation of phosphatidylinositol 3-kinase–AKTs–mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.

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Supported by the National Center of Neurology and Psychiatry Intramural Research grants 27-7 (E.N., M.I.) and 28-4 (M.H., M.I.) for Neurological and Psychiatric Disorders, the Japan Society for the Promotion of Science grant-in-aid 25670486 for Challenging Exploratory Research (M.I.), and the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics grant-in-aid (M.I.).

Disclosures: None declared.

Current address of T.Ot., Epilepsy Hospital Bethel Japan, Sendai, Japan; of T.K., National Hospital Organization Nara Medical Center, Nara, Japan; of A.T., National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan.