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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; [...]

An integrated genetic analysis of epileptogenic brain malformed lesions

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  • Medientyp: E-Artikel
  • Titel: An integrated genetic analysis of epileptogenic brain malformed lesions
  • Beteiligte: 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; [...]
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Acta Neuropathologica Communications
  • Sprache: Englisch
  • DOI: 10.1186/s40478-023-01532-x
  • ISSN: 2051-5960
  • Schlagwörter: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Focal 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 <jats:italic>MTOR</jats:italic>, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of <jats:italic>MAP2K1</jats:italic> and <jats:italic>PTPN11</jats:italic> involved in the RAS/MAPK pathway were detected. The in-frame deletions of <jats:italic>MTOR</jats:italic> and <jats:italic>MAP2K1</jats:italic> in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the <jats:italic>PTPN11</jats:italic> 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.</jats:p>
  • Zugangsstatus: Freier Zugang