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ワタナベ ケイスケ
渡辺 啓介 所属 新潟薬科大学 医療技術学部 臨床検査学科 職種 教授 |
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| 言語種別 | 英語 |
| 発行・発表の年月 | 2015/09 |
| 形態種別 | 論文 |
| 査読 | 査読あり |
| 標題 | Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb |
| 執筆形態 | 共著 |
| 掲載誌名 | ANNALS OF NEUROLOGY |
| 掲載区分 | 国外 |
| 出版社・発行元 | WILEY-BLACKWELL |
| 巻・号・頁 | 78(3),pp.375-386 |
| 著者・共著者 | Mitsuko Nakashima,Hirotomo Saitsu,Nobuyuki Takei,Jun Tohyama,Mitsuhiro Kato,Hiroki Kitaura,Masaaki Shiina,Hiroshi Shirozu,Hiroshi Masuda,Keisuke Watanabe,Chihiro Ohba,Yoshinori Tsurusaki,Noriko Miyake,Yingjun Zheng,Tatsuhiro Sato,Hirohide Takebayashi,Kazuhiro Ogata,Shigeki Kameyama,Akiyoshi Kakita,Naomichi Matsumoto |
| 概要 | ObjectiveFocal 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.
MethodsWe 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. ResultsWe 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. InterpretationWe 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 |
| DOI | 10.1002/ana.24444 |
| ISSN | 0364-5134/1531-8249 |
| PMID | 26018084 |