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Uncover pathomechanism of megalencephaly using brain organdies.

Research Project

Project/Area Number 20H03646
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionNagoya City University

Principal Investigator

Saitoh Shinji  名古屋市立大学, 医薬学総合研究院(医学), 教授 (00281824)

Co-Investigator(Kenkyū-buntansha) 加藤 洋一  名古屋市立大学, 医薬学総合研究院(医学), 教授 (10815161)
大石 久史  名古屋市立大学, 医薬学総合研究院(医学), 教授 (30375513)
嶋田 逸誠  名古屋市立大学, 医薬学総合研究院(医学), 講師 (40833265)
宮 冬樹  慶應義塾大学, 医学部(信濃町), 准教授 (50415311)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2023: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Keywords巨脳症 / 脳オルガノイド / 神経発生 / 外側放射状グリア / 神経幹細胞 / オルガノイド / iPS細胞
Outline of Research at the Start

本研究では巨脳症の発症機序を患者集積、モデルマウスの作成、脳オルガノイド作成により統合的に解析する。患者解析は臨床情報の集積に加えて、パネル解析、生化学的解析、ゲノム解析を用いて総合的に実施する。そして、機能的に巨脳症の分類を目指す。発症メカニズムについてはモデルマウスの作成と解析、および患者由来iPS細胞や遺伝子改変ヒトiPS細胞を用いたオルガノイドの作成と解析を行う。異なった解析系を組み合わせることで統合的な巨脳症発症メカニズムの解析を目指す。

Outline of Final Research Achievements

We collected 89 cases of megalencephaly patients and identified causative variants in 42 case (47.1%), constructing a megalencephaly registry.
We created MYCN-KI mice introducing mutations identified in megelencephaly patients and MYCN-hKO mice with heterozygous loss-of-function mutations in MYCN. Both models reproduced brain size enlargement and reduction, recapitulating the human disease.
We edited the genome of iPS cells to introduce mutations in PNPLA8, MYCN, and SZT2, establishing cell lines. From each, we induced differentiation into brain organoids and conducted analyses, revealing the association between brain size, sub ventricular zone (SVZ) size, and the number of outer radial glial cells (oRG) in the SVZ.

Academic Significance and Societal Importance of the Research Achievements

巨脳症の発症メカニズムを患者集積、マウスモデル、脳オルガノイドの組み合わせにより解明した。巨脳症は脳サイズが大きくなり、様々な神経症状を呈する疾患であり、治療法は存在しない。そのメカニズムを解明することで、創薬への基盤を築くことができた。さらに、脳サイズはヒトの進化の理解に重要である。脳発生における外側放射状グリアが脳サイズ決定に重要な役割を果たしていることを明らかにした今回の研究は、ヒト進化の理解への貢献が期待できる。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (35 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (1 results) Journal Article (21 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 21 results,  Open Access: 8 results) Presentation (13 results) (of which Int'l Joint Research: 6 results)

  • [Int'l Joint Research] INSERM/CHU Dijon Bourgogne/CHU Rennes(フランス)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome2023

    • Author(s)
      Nishio Yosuke、Kato Kohji、Tran Mau-Them Frederic、Futagawa Hiroshi、Quelin Chloe、Masuda Saori、Vitobello Antonio、Otsuji Shiomi、Shawki Hossam H.、Oishi Hisashi、Thauvin-Robinet Christel、Takenouchi Toshiki、Kosaki Kenjiro、Takahashi Yoshiyuki、Saitoh Shinji
    • Journal Title

      Human Genetics and Genomics Advances

      Volume: 4 Issue: 4 Pages: 100238-100238

    • DOI

      10.1016/j.xhgg.2023.100238

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants2023

    • Author(s)
      Inoue Yuta、Tsuchida Naomi、Okamoto Nobuhiko、Shuichi Shimakawa、Ohashi Kei、Saitoh Shinji、Ogawa Atsushi、Hamada Keisuke、Sakamoto Masamune、Miyake Noriko、Hamanaka Kohei、Fujita Atsushi、Koshimizu Eriko、Miyatake Satoko、Mizuguchi Takeshi、Ogata Kazuhiro、Uchiyama Yuri、Matsumoto Naomichi
    • Journal Title

      Clinical Genetics

      Volume: 103 Issue: 5 Pages: 590-595

    • DOI

      10.1111/cge.14292

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy2022

    • Author(s)
      Sakamoto M et al, Saitoh Sは30番目
    • Journal Title

      Genetics in Medicine

      Volume: 24 Issue: 12 Pages: 2453-2463

    • DOI

      10.1016/j.gim.2022.08.007

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome2022

    • Author(s)
      Otsuji Shiomi、Nishio Yosuke、Tsujita Maki、Rio Marlene、Huber Celine、Anton-Plagaro Carlos、Mizuno Seiji、Kawano Yoshihiko、Miyatake Satoko、Simon Marleen、van Binsbergen Ellen、van Jaarsveld Richard H、Matsumoto Naomichi、Cormier-Daire Valerie、J.Cullen Peter、Saitoh Shinji、Kato Kohji
    • Journal Title

      Journal of Medical Genetics

      Volume: 60 Issue: 4 Pages: 359-367

    • DOI

      10.1136/jmg-2022-108602

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Angelman syndrome with mosaic paternal uniparental disomy suggestive of mitotic nondisjunction2022

    • Author(s)
      Fujimoto Masanori、Nakamura Yuji、Iwaki Toshihiko、Sato Emi、Ieda Daisuke、Hattori Ayako、Shiraki Anna、Mizuno Seiji、Saitoh Shinji
    • Journal Title

      Journal of Human Genetics

      Volume: 68 Issue: 2 Pages: 87-90

    • DOI

      10.1038/s10038-022-01088-z

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Whole-exome analysis of 177 pediatric patients with undiagnosed diseases.2022

    • Author(s)
      Narita K, Muramatsu H, Narumi S, Nkawa T, Okumura A, et al.
    • Journal Title

      Sci Rep

      Volume: 12(1) Issue: 1 Pages: 14589-14589

    • DOI

      10.1038/s41598-022-14161-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Utility of tissue-specific gene expression scores for gene prioritization in Mendelian diseases2022

    • Author(s)
      Kato Daiki、Mitsuhashi Satomi、Miya Fuyuki、Saitoh Shinji、Okamoto Nobuhiko、Tsunoda Tatsuhiko、Kochi Yuta
    • Journal Title

      Journal of Human Genetics

      Volume: 67 Issue: 12 Pages: 739-742

    • DOI

      10.1038/s10038-022-01071-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The iodide transporter Slc26a7 impacts thyroid function more strongly than Slc26a4 in mice.2022

    • Author(s)
      Yamaguchi N, Suzuki A, Yoshida A, Tanaka T, Aoyama K, Oishi H, Hara Y, Ogi T, Amano I, Kameo S, Koibuchi N, Shibata Y, Ugawa S, Mizuno H, Saitoh S
    • Journal Title

      Sci Rep.

      Volume: 12 Issue: 1 Pages: 11259-11259

    • DOI

      10.1038/s41598-022-15151-4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-term follow-up of a patient with autosomal dominant lower extremity-predominant spinal muscular atrophy-2 due to a BICD2 variant2022

    • Author(s)
      Yamamoto Kosuke、Ohashi Kei、Fujimoto Masanori、Ieda Daisuke、Nakamura Yuji、Hattori Ayako、Kaname Tadashi、Ieda Kuniko、Nishino Ichizo、Saitoh Shinji
    • Journal Title

      Brain and Development

      Volume: 44 Issue: 8 Pages: 578-582

    • DOI

      10.1016/j.braindev.2022.04.006

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hemorrhagic shock and encephalopathy syndrome in a patient with a de novo heterozygous variant in KIF1A2022

    • Author(s)
      Isobe Kouji、Ieda Daisuke、Miya Fuyuki、Miyachi Rieko、Otsuji Shiomi、Asai Masami、Tsunoda Tatsuhiko、Kosaki Kenjiro、Hattori Ayako、Saitoh Shinji、Mizuno Mihoko
    • Journal Title

      Brain and Development

      Volume: 44 Issue: 3 Pages: 249-253

    • DOI

      10.1016/j.braindev.2021.11.007

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Four pedigrees with aminoacyl-tRNA synthetase abnormalities2021

    • Author(s)
      Okamoto Nobuhiko、Miya Fuyuki、Tsunoda Tatsuhiko、Kanemura Yonehiro、Saitoh Shinji、Kato Mitsuhiro、Yanagi Kumiko、Kaname Tadashi、Kosaki Kenjiro
    • Journal Title

      Neurological Sciences

      Volume: 43 Issue: 4 Pages: 2765-2774

    • DOI

      10.1007/s10072-021-05626-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Utility of breakpoint‐specific nested polymerase chain reaction for the diagnosis of Emanuel syndrome2021

    • Author(s)
      Hayakawa Kozue、Kawase Koya、Fujimoto Masanori、Nakamura Yuji、Saitoh Shinji
    • Journal Title

      Pediatrics International

      Volume: 63 Issue: 12 Pages: 1534-1536

    • DOI

      10.1111/ped.14644

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A case of ATR-X syndrome with mitochondrial respiratory chain dysfunction2021

    • Author(s)
      Aiba Kaori、Nakamura Yuji、Sugimoto Mari、Yatsuka Yukiko、Okazaki Yasushi、Murayama Kei、Ohtake Akira、Yokochi Kenji、Saitoh Shinji
    • Journal Title

      European Journal of Medical Genetics

      Volume: 64 Issue: 8 Pages: 104251-104251

    • DOI

      10.1016/j.ejmg.2021.104251

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] SCN8A-related developmental and epileptic encephalopathy with ictal asystole requiring cardiac pacemaker implantation2021

    • Author(s)
      Negishi Yutaka、Aoki Yusuke、Itomi Kazuya、Yasuda Kazushi、Taniguchi Hiroaki、Ishida Atsushi、Arakawa Takeshi、Miyamoto Sachiko、Nakashima Mitsuko、Saitsu Hirotomo、Saitoh Shinji
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 7 Pages: 804-808

    • DOI

      10.1016/j.braindev.2021.03.004

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] <i>Itpr1</i> regulates the formation of anterior eye segment tissues derived from neural crest cells2021

    • Author(s)
      Kinoshita Akira、Ohyama Kaname、Tanimura Susumu、Matsuda Katsuya、Kishino Tatsuya、Negishi Yutaka、Asahina Naoko、Shiraishi Hideaki、Hosoki Kana、Tomiwa Kiyotaka、Ishihara Naoko、Mishima Hiroyuki、Mori Ryoichi、Nakashima Masahiro、Saitoh Shinji、Yoshiura Koh-ichiro
    • Journal Title

      Development

      Volume: 148 Issue: 16 Pages: 188755-188755

    • DOI

      10.1242/dev.188755

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability2021

    • Author(s)
      Okamoto Nobuhiko、Miya Fuyuki、Kitai Yukihiro、Tsunoda Tatsuhiko、Kato Mitsuhiro、Saitoh Shinji、Kanemura Yonehiro、Kosaki Kenjiro
    • Journal Title

      Neurological Sciences

      Volume: - Issue: 7 Pages: 2975-2978

    • DOI

      10.1007/s10072-021-05152-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings2021

    • Author(s)
      Ohashi K, Fukuhara S, Miyachi T, Asai T, Imaeda M, Goto M, Kurokawa Y, Anzai T, Tsurusaki Y, Miyake N, Matsumoto N, Yamagata T, Saitoh S
    • Journal Title

      J Autism Dev Disord

      Volume: なし Issue: 12 Pages: 4655-4662

    • DOI

      10.1007/s10803-021-04910-3

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant2021

    • Author(s)
      Hori Ikumi、Ieda Daisuke、Ito Shogo、Ebe Seimi、Nakamura Yuji、Ohashi Kei、Aoyama Kohei、Hattori Ayako、Kokubo Minoru、Saitoh Shinji
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 4 Pages: 590-595

    • DOI

      10.1016/j.braindev.2020.12.008

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel missense variant in CUL3 shows altered binding ability to BTB-adaptor proteins leading to diverse phenotypes of CUL3-related disorders2021

    • Author(s)
      Kato Kohji、Miya Fuyuki、Oka Yasuyoshi、Mizuno Seiji、Saitoh Shinji
    • Journal Title

      Journal of Human Genetics

      Volume: 66 Issue: 5 Pages: 491-498

    • DOI

      10.1038/s10038-020-00868-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] De novo 2q36.3q37.1 deletion encompassing TRIP12 and NPPC yields distinct phenotypes2020

    • Author(s)
      Kondo Yuto、Aoyama Kohei、Suzuki Hisato、Hattori Ayako、Hori Ikumi、Ito Koichi、Yoshida Aya、Koroki Mari、Ueda Kentaro、Kosaki Kenjiro、Saitoh Shinji
    • Journal Title

      Human Genome Variation

      Volume: 7 Issue: 1 Pages: 19-19

    • DOI

      10.1038/s41439-020-0107-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prenatal clinical manifestations in individuals with COL4A1/2 variants2020

    • 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

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Gain-of-function MYCN causes a megalencephaly- polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.2023

    • Author(s)
      Nishio Y, Kato K, Mau-Them Frederic T, Futagawa H, Quelin C, Masuda S, Vitobello A, Otsuji S, Shawki HH, Oishi H, Thauvin-Robinet C, Takenouchi T, Kosaki K, Takahashi Y, Saitoh S.
    • Organizer
      American Society of Human Genetics 2023 meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Gain-of-function MYCN causes a megalencephaly- polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome.2023

    • Author(s)
      Nishio Y, Kato K, Mau-Them Frederic T, Futagawa H, Quelin C, Masuda S, Vitobello A, Otsuji S, Shawki HH, Oishi H, Thauvin-Robinet C, Takenouchi T, Kosaki K, Takahashi Y, Saitoh S.
    • Organizer
      Asian Society of Pediatric Research 2023 meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome.2022

    • Author(s)
      Otsuji S, Nishio Y, Tsujita M, Rio M, Huber C, Anton-Plagaro C, Mizuno S, Kawano Y, Miyatake S, Simon M, van Binsbergen E, van Jaarsveld RH, Matsumoto N, Cormier-Daire V, J Cullen P, Saitoh S, Kato K
    • Organizer
      American Society of Human Genetics Annual Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Biallelic variants in PNPLA8 disrupt cortical gyrification through aberrant mitochondrial dynamics.2022

    • Author(s)
      Nakamura Y, Shimada IS, Fujimoto M, Sato E, Ieda D, Hattori A, Miya F, Tsunoda T, Okubo Y, Haginoya K, Koshimizu E, Miyatake S, Matsumoto N, Arioka Y, Ozaki N, Kato Y, Saitoh S.
    • Organizer
      第64回日本小児神経学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Angelman syndrome with mosaic paternal uniparental disomy caused by mitotic nondisjunction.2022

    • Author(s)
      Fujimoto M, Nakamura Y, Iwaki T, Sato E, Ieda D, Hattori A, Shiraki A, Mizuho S, Saitoh S.
    • Organizer
      American Society of Human Genetics Annual Meeting 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PNPLA8 deficiency induces microcephaly and reduces neurogenesis in a brain organoid model.2021

    • Author(s)
      Nakamura Y, Shimada I, Fujimoto M, Sato E, Ieda D, Hattori A, Miya F, Tsunoda T, Okubo Y, Haginoya K, Koshimizu E, Miyatake S, Matsumoto N, Arioka Y, Ozaki N, Kato Y, Saitoh S
    • Organizer
      第63回日本小児神経学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] NAA15遺伝子の変異に伴う重度知的発達症ならびに自閉スペクトラム症の男児の一例.2021

    • Author(s)
      大橋圭、川岡奈緒実、谷合弘子、三宅紀子、松本直通、齋藤伸治
    • Organizer
      第63回日本小児神経学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ミトコンドリアホスホリパーゼPNPLA8機能喪失は神経系細胞においてミトコンドリアダイナミクス異 常を引き起こす.2021

    • Author(s)
      中村勇治、嶋田逸誠、加藤洋一、齋藤伸治
    • Organizer
      第66回日本人類遺伝学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] VPS35L pathogenic variants cause 3C/Ritscher-Scinzel-like syndrome: Description of two novel cases confirming the pathogenicity and clinical diversity.2021

    • Author(s)
      Otsuji S, Kato K, Lequesne CH, Mizuno S, Rio M, Miyatake S, Nishio Y, Matsumoto N, Cormier-Daire V, Saitoh
    • Organizer
      American Society of Human Genetics Virtual Meeting 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MYCN gain-of-function variants induce excess proliferation of neurons and cause a novel megalencephaly syndrome.2021

    • Author(s)
      Yosuke Nishio, Kohji Kato, Tran Mau-Them Frederic, Shiomi Otsuji, Chloe Quelin, Hisashi Oishi, Yoshiyuki Takahashi, Shinji Saitoh
    • Organizer
      American Society of Human Genetics Virtual Meeting 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mild Phenotypic features associated with non-truncating UBE3A mutations in Angelman syndrome.2020

    • Author(s)
      Yuji Nakamura, Kana Hosoki, Daisuke Ieda, Ikumi Hori, Yutaka Negishi, Ayako Hattori, Shinji Saitoh
    • Organizer
      第62回日本小児神経学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 当院でエキソーム解析を実施した小児神経疾患症例の臨床的検討.2020

    • Author(s)
      堀いくみ, 宮冬樹, 中島光子, 中村勇治, 家田大輔, 大橋圭, 根岸豊, 服部文子, 安藤直樹, 角田達彦, 才津浩智, 金村米博, 小崎健次郎, 齋藤伸治
    • Organizer
      第62回日本小児神経学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] A novel case with biallelic VPS35L variants confirms VPS35L as a causative gene of 3C/Ritscher-Schinzel-like syndrome.2020

    • Author(s)
      Shiomi Otsuji, Kohji Kato, Seiji Mizuno, Satoko Miyatake, Naomichi Matsumoto, Shinji Saitoh
    • Organizer
      第65回人類遺伝学会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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