Acta Neuropathologica Communications (Mar 2023)
An integrated genetic analysis of epileptogenic brain malformed lesions
- Atsushi Fujita,
- Mitsuhiro Kato,
- Hidenori Sugano,
- Yasushi Iimura,
- Hiroharu Suzuki,
- Jun Tohyama,
- Masafumi Fukuda,
- Yosuke Ito,
- Shimpei Baba,
- Tohru Okanishi,
- Hideo Enoki,
- Ayataka Fujimoto,
- Akiyo Yamamoto,
- Kentaro Kawamura,
- Shinsuke Kato,
- Ryoko Honda,
- Tomonori Ono,
- Hideaki Shiraishi,
- Kiyoshi Egawa,
- Kentaro Shirai,
- Shinji Yamamoto,
- Itaru Hayakawa,
- Hisashi Kawawaki,
- Ken Saida,
- Naomi Tsuchida,
- Yuri Uchiyama,
- Kohei Hamanaka,
- Satoko Miyatake,
- Takeshi Mizuguchi,
- Mitsuko Nakashima,
- Hirotomo Saitsu,
- Noriko Miyake,
- Akiyoshi Kakita,
- Naomichi Matsumoto
Affiliations
- Atsushi Fujita
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine
- Hidenori Sugano
- Department of Neurosurgery, Epilepsy Center, Juntendo University
- Yasushi Iimura
- Department of Neurosurgery, Epilepsy Center, Juntendo University
- Hiroharu Suzuki
- Department of Neurosurgery, Epilepsy Center, Juntendo University
- Jun Tohyama
- Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital
- Masafumi Fukuda
- Department of Functional Neurosurgery, Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital
- Yosuke Ito
- Department of Functional Neurosurgery, Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital
- Shimpei Baba
- Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital
- Tohru Okanishi
- Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University
- Hideo Enoki
- Department of Pediatrics, Kawasaki Medical School
- Ayataka Fujimoto
- Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital
- Akiyo Yamamoto
- Department of Pediatrics, Sapporo Medical University School of Medicine
- Kentaro Kawamura
- Department of Pediatrics, Sapporo Medical University School of Medicine
- Shinsuke Kato
- Department of Pediatrics, Sapporo Medical University School of Medicine
- Ryoko Honda
- Department of Pediatrics, National Hospital Organization Nagasaki Medical Center
- Tomonori Ono
- Epilepsy Center, National Hospital Organization Nagasaki Medical Center
- Hideaki Shiraishi
- Department of Pediatrics, Hokkaido University Graduate School of Medicine
- Kiyoshi Egawa
- Department of Pediatrics, Hokkaido University Graduate School of Medicine
- Kentaro Shirai
- Department of Pediatrics, Tsuchiura Kyodo General Hospital
- Shinji Yamamoto
- Department of Neurosurgery, Tsuchiura Kyodo General Hospital
- Itaru Hayakawa
- Division of Neurology, National Center for Child Health and Development
- Hisashi Kawawaki
- Department of Pediatric Neurology, Children’s Medical Center, Osaka City General Hospital
- Ken Saida
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Naomi Tsuchida
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Yuri Uchiyama
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Kohei Hamanaka
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Satoko Miyatake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Takeshi Mizuguchi
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Mitsuko Nakashima
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Hirotomo Saitsu
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- Akiyoshi Kakita
- Department of Pathology, Brain Research Institute, Niigata University
- Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine
- DOI
- https://doi.org/10.1186/s40478-023-01532-x
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 11
Abstract
Abstract 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 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.
Keywords
