Identification of a novel gene for early-onset epilepsy and elucidation of its pathogenic mechanism

• Project/Area Number: 19K16921
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Yokohama City University
• Principal Investigator: IMAMURA (KOSHIMIZU) Eriko 横浜市立大学, 医学研究科, 特任助教 (80637877)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 進行性ミオクローヌスてんかん / 全エクソームシーケンス / ゼブラフィッシュ / てんかん / 全エクソーム解析

Outline of Research at the Start

申請者はてんかん発作を呈した症例に対して次世代シークエンサーを用いた全エクソーム解析を施行し、てんかん発作と重度の知的障害を呈した1家系から新規の責任遺伝子候補となる「SEMAXX (仮称)」を単離した。SEMAXX変異は3家系から3変異見出され、すべてde novoで生じたトランケート型変異（タンパク合成が途中で中断される変異）であった。SEMAXXは神経軸索ガイダンスの伸長抑制作用を持つため、抑制性シナプスの機能欠損による神経細胞の過活動が本疾患の原因であると考えられた。本研究では、てんかん発症の新規責任遺伝子としてSEMAXX遺伝子を同定し、本症の発症機構を解明することを目的とした。

Outline of Final Research Achievements

In order to identify for novel candidate genes causing developmental and epileptic encephalopathies, we searched for genetic mutations using whole-exome sequencing data of 6,045 patients. As a result, we detected de novo mutations in SEMA6B, a novel gene, in five patients. These mutations resulted in a truncated protein and were all located in the last exon, which was prevented nonsense mediated mRNA decay. The effect of the mutations was verified by an in vivo model system using zebrafish, which mimicked neuronal abnormalities and myoclonus epilepsy-like behavior in humans. Thus, we hypothesized that the production of an abnormal truncated form of SEMA6B protein by the gene mutation is the cause of this disease.

Academic Significance and Societal Importance of the Research Achievements

てんかんの発症はイオンチャネルに関わる遺伝子の異常が主な原因とされているが、本研究により新たに同定されたSEMA6B遺伝子は、神経軸索ガイダンスの伸長抑制作用を持つ。SEMA6B遺伝子を新規責任遺伝子として同定したことで、てんかんを引き起こす新たな発症経路が中枢神経系の発達と関連していることを明らかにした。本研究の成果は、早期発症型てんかんの分子診断や病態メカニズムの解明、治療薬の開発に寄与する。

Research Products

• [Int'l Joint Research] Rambam Health Care Campus(イスラエル)
• [Int'l Joint Research] Hospital Kuala Lumpur(マレーシア)
• [Journal Article] De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy (2021)
  • Author(s): Itai T, Hamanaka K, Sasaki K, Saitsu H, Miyatake S, Matsumoto N et al.
  • Journal Title: Hum Mutat Volume: 42 Issue: 1 Pages: 66-76
  • DOI: 10.1002/humu.24130
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] De novo ATP1A3 variants cause polymicrogyria (2021)
  • Author(s): Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
  • Journal Title: Science Advances Volume: 7 Issue: 13 Pages: 2368-2368
  • DOI: 10.1126/sciadv.abd2368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features (2020)
  • Author(s): Lehalle Daphne, Vabres Pierre, Sorlin Arthur, Torti Erin, Abe Yuichi, Koshimizu Eriko, Miyakate Sakoto, St-Onge Judith, Thevenon Julien, Verdura Edgard, Whelan Habela Christa, Zacher Pia, Riviere Jean-Baptiste, Thauvin-Robinet Christel, Betschinger Joerg, Faivre Laurence, et al.
  • Journal Title: Journal of Medical Genetics Volume: 57 Issue: 12 Pages: 808-819
  • DOI: 10.1136/jmedgenet-2019-106508
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prenatal clinical manifestations in individuals with COL4A1/2 variants (2020)
  • Author(s): Itai T, Miyatake S, Taguri M, Nakashima M, Saitsu H, Matsumoto N et al.
  • Journal Title: J Med Genet Volume: 0 Issue: 8 Pages: 106896-106896
  • DOI: 10.1136/jmedgenet-2020-106896
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy (2020)
  • Author(s): Sakamoto Masamune、Iwama Kazuhiro、Sekiguchi Futoshi、Mashimo Hideaki、Kumada Satoko、Ishigaki Keiko、Okamoto Nobuhiko、Behnam Mahdiyeh、Ghadami Mohsen、Koshimizu Eriko、Miyatake Satoko、Mitsuhashi Satomi、Mizuguchi Takeshi、Takata Atsushi、Saitsu Hirotomo、Miyake Noriko、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 4 Pages: 401-407
  • DOI: 10.1038/s10038-020-00853-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficient detection of copy‐number variations using exome data: Batch‐ and sex‐based analyses (2020)
  • Author(s): Uchiyama Yuri、Yamaguchi Daisuke、Iwama Kazuhiro, et al.
  • Journal Title: Human Mutation Volume: 42 Issue: 1 Pages: 50-65
  • DOI: 10.1002/humu.24129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy (2020)
  • Author(s): Hamanaka Kohei、Imagawa Eri、Koshimizu Eriko、Miyatake Satoko、Tohyama Jun、Yamagata Takanori、Miyauchi Akihiko、Ekhilevitch Nina、Nakamura Fumio、Kawashima Takeshi、Takata Atsushi、Miyake Noriko、Matsumoto Naomichi et al.,
  • Journal Title: The American Journal of Human Genetics Volume: 106(4) Issue: 4 Pages: 549-558
  • DOI: 10.1016/j.ajhg.2020.02.011
  • Peer Reviewed / Int'l Joint Research
• [Presentation] SEMA6B遺伝子変異は進行性ミオクローヌスてんかんを引き起こす (2020)
  • Author(s): 輿水江里子, 濱中耕平, 今川英里, 高田篤, 遠山潤, 山形崇倫, 宮内彰彦, Nina Ekhilevitch, Gaik-Siew Ch'ng, 中島光子, 才津浩智, 水口 剛, 宮武聡子, 三宅紀子, 松本直通
  • Organizer: 日本人類遺伝学会第65回大会
• [Remarks] 進行性ミオクローヌスてんかんの原因遺伝子を明らかに!
  • URL: https://www.yokohama-cu.ac.jp/amedrc/news/202003hamanaka_AJHG.html
• [Remarks] 進行性ミオクローヌスてんかんの原因遺伝子を明らかに
  • URL: https://www.amed.go.jp/news/release_20200313.html