An integrated genetic analysis of epileptogenic brain malformed lesions
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Published:2023-03-02
Issue:1
Volume:11
Page:
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ISSN:2051-5960
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Container-title:Acta Neuropathologica Communications
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language:en
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Short-container-title:acta neuropathol commun
Author:
Fujita Atsushi, Kato Mitsuhiro, Sugano Hidenori, Iimura Yasushi, Suzuki Hiroharu, Tohyama Jun, Fukuda Masafumi, Ito Yosuke, Baba Shimpei, Okanishi Tohru, Enoki Hideo, Fujimoto Ayataka, Yamamoto Akiyo, Kawamura Kentaro, Kato Shinsuke, Honda Ryoko, Ono Tomonori, Shiraishi Hideaki, Egawa Kiyoshi, Shirai Kentaro, Yamamoto Shinji, Hayakawa Itaru, Kawawaki Hisashi, Saida Ken, Tsuchida Naomi, Uchiyama Yuri, Hamanaka Kohei, Miyatake Satoko, Mizuguchi Takeshi, Nakashima Mitsuko, Saitsu Hirotomo, Miyake Noriko, Kakita Akiyoshi, Matsumoto NaomichiORCID
Abstract
AbstractFocal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.
Funder
Japan Agency for Medical Research and Development JSPS KAKENHI Takeda Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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