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Somatic Mutations in the MTOR gene cause focal cortical dysplasia type II b
Author(s) -
Nakashima Mitsuko,
Saitsu Hirotomo,
Takei Nobuyuki,
Tohyama Jun,
Kato Mitsuhiro,
Kitaura Hiroki,
Shiina Masaaki,
Shirozu Hiroshi,
Masuda Hiroshi,
Watanabe Keisuke,
Ohba Chihiro,
Tsurusaki Yoshinori,
Miyake Noriko,
Zheng Yingjun,
Sato Tatsuhiro,
Takebayashi Hirohide,
Ogata Kazuhiro,
Kameyama Shigeki,
Kakita Akiyoshi,
Matsumoto Naomichi
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24444
Subject(s) - somatic cell , pi3k/akt/mtor pathway , cortical dysplasia , germline mutation , biology , microbiology and biotechnology , cancer research , mutation , gene , genetics , signal transduction , neuroscience , epilepsy
Objective Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. Methods We collected a total of 24 blood‐brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole‐exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. Results We identified four lesion‐specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. Interpretation We found low‐prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. Ann Neurol 2015;78:375–386