Am J Pathol. 2017 May;187(5):1177-1185. doi: 10.1016/j.ajpath.2017.01.015.

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


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.


国立精神・神経医療研究センター病院で、難治性てんかんの外科治療として半球離断術を受けた患者で、HME症例にmTOR遺伝子のミスセンス変異を脳特異的な体細胞変異として検出した。変異mTORベクター導入HeLa細胞では、巨細胞化を示し、MTORの下流分子S6と4EBP1のリン酸化亢進を認め、MTOR活性化を示した。E14.5マウス胎仔脳室内ベクター移植では、Wild-type mTORベクターと変異mTORベクター導入個体ではEGFP陽性細胞の巨細胞化に加え、皮質下層への貯留が見られ、その程度は患者変異mTORベクターを導入したマウス大脳皮質でより顕在化していた。

PMID:  28427592