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2016 Fiscal Year Annual Research Report

elucidation of a mechanism of developmental disorder caused genome copy number aberration

Research Project

Project/Area Number 24791090
Research InstitutionTokyo Women's Medical University

Principal Investigator

下島 圭子  東京女子医科大学, 医学部, 特任助教 (30578935)

Project Period (FY) 2012-04-01 – 2017-03-31
KeywordsiPS細胞 / 発達障害 / 神経細胞遊走障害 / ニューロン / シナプス
Outline of Annual Research Achievements

アレイCGH解析によりゲノムコピー数異常が発生要因と同定された発達障害患者から疾患iPS細胞を樹立し、神経系細胞へ分化誘導させて病態解析を行い、発症メカニズムを解明することが本研究の目的である。前年度までは神経分化の時間的経過に沿って網羅的な遺伝子解析を行い、疾患特異的な遺伝子発現を同定した。また、神経分化誘導過程でマウスアストロサイトを共培養させることで、長期培養によって成熟したニューロンまで分化させることに成功した。患者由来iPS細胞を用いてニューロンを解析したところ、スパインの形成不全と活動電流の減弱を認めた。
今年度は前年度に引き続き解析数を増やして実験を追加した。ミクロレベルでの疾患特異的な変化の有無を同定するため、スパインの解析として免疫染色でSynapsin1とPSD95で共染色部位のDot数をカウントし、シナプスにおける密度を計算した。現在まだ解析を続けている段階であるが、疾患由来のニューロンでは密度が正常に比べて小さいという結果が得られている。
さらに、iPS細胞をシングルセル培養に切り替えて、レンチウイルスベクターを用いて正常iPS細胞と疾患iPS細胞をそれぞれ異なる蛍光色素(DsRed・EGFP)で標識した。それらのiPS細胞を同一のDishで神経分化を行った。この方法によって、培養状態を統一でき、神経ネットワークの成熟度の影響を無視できる状況でのニューロンにおける疾患特異的変化の有無を観察した。蛍光色素の導入に時間がかかり、現在培養を継続している状態であるため、今後結果をまとめて公表する予定である。
さらに、発達障害を来たした患者を新たに次世代シークエンサーやアレイCGHを用いた遺伝学的解析によって遺伝学的異常を認め、論文報告した。
今後も病態解析の有効なツールとしてiPS細胞技術を用いて解析を行う予定である。

  • Research Products

    (28 results)

All 2017 2016

All Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 14 results,  Acknowledgement Compliant: 14 results,  Open Access: 4 results) Presentation (12 results) (of which Int'l Joint Research: 7 results) Book (2 results)

  • [Journal Article] A 10q21.3q22.2 microdeletion identified in a patient with severe developmental delay and multiple congenital anomalies including congenital heart defects.2017

    • Author(s)
      Shimojima K, Okamoto N, Yamamoto T.
    • Journal Title

      Congenit Anom (Kyoto).

      Volume: 印刷中 Pages: 印刷中

    • DOI

      10.1111/cga.12221.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent intragenic deletions due to parental mosaicism.2017

    • Author(s)
      Yamamoto T, Shimojima K, Ondo Y, Shimakawa S, Okamoto N.
    • Journal Title

      Am J Med Genet A.

      Volume: 印刷中 Pages: 印刷中

    • DOI

      10.1002/ajmg.a.38168.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] An Xq22.1q22.2 nullisomy in a male patient with severe neurological impairment.2017

    • Author(s)
      Shirai K, Higashi Y, Shimojima K, Yamamoto T.
    • Journal Title

      Am J Med Genet A.

      Volume: 173(4) Pages: 1124-1127

    • DOI

      10.1002/ajmg.a.38134.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] A novel COL1A1 mutation in a family with osteogenesis imperfecta associated with phenotypic variabilities.2017

    • Author(s)
      Seto T, Yamamoto T, Shimojima K, Shintaku H.
    • Journal Title

      Hum Genome Var.

      Volume: Mar 16;4 Pages: 17007

    • DOI

      10.1038/hgv.2017.7.

    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A 7q31.33q32.1 microdeletion including LRRC4 and GRM8 is associated with severe intellectual disability and characteristics of autism.2017

    • Author(s)
      Sangu N, Shimojima K, Takahashi Y, Ohashi T, Tohyama J, Yamamoto T.
    • Journal Title

      Hum Genome Var.

      Volume: Feb 9;4 Pages: 17001

    • DOI

      10.1038/hgv.2017.1.

    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Neurological manifestations of 2q31 microdeletion syndrome.2017

    • Author(s)
      Okamoto N, Kimura S, Shimojima K, Yamamoto T.
    • Journal Title

      Congenit Anom (Kyoto).

      Volume: 印刷中 Pages: 印刷中

    • DOI

      10.1111/cga.12212.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus-Merzbacher disease.2017

    • Author(s)
      Lu Y, Shimojima K, Sakuma T, Nakaoka S, Yamamoto T.
    • Journal Title

      Hum Genome Var.

      Volume: Jan 5;4: Pages: 16044

    • DOI

      10.1038/hgv.2016.44.

    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan.2017

    • Author(s)
      Yamamoto T, Shimojima K, Matsufuji M, Mashima R, Sakai E, Okuyama T.
    • Journal Title

      Brain Dev.

      Volume: 39(5) Pages: 422-425

    • DOI

      10.1016/j.braindev.2016.12.004.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Possible genes responsible for developmental delay observed in patients with rare 2q23q24 microdeletion syndrome: Literature review and description of an additional patient.2017

    • Author(s)
      Shimojima K, Okamoto N, Yamamoto T.
    • Journal Title

      Congenit Anom (Kyoto).

      Volume: 印刷中 Pages: 印刷中

    • DOI

      10.1111/cga.12205.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Loss-of-function mutations and global rearrangements in GPC3 in patients with Simpson-Golabi-Behmel syndrome.2016

    • Author(s)
      Shimojima K, Ondo Y, Nishi E, Mizuno S, Ito M, Ioi A, Shimizu M, Sato M, Inoue M, Okamoto N, Yamamoto T.
    • Journal Title

      Hum Genome Var.

      Volume: Oct 13;3 Pages: 16033

    • DOI

      10.1038/hgv.2016.33

    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations.2016

    • Author(s)
      Hamatani M, Jingami N, Tsurusaki Y, Shimada S, Shimojima K, Asada-Utsugi M, Yoshinaga K, Uemura N, Yamashita H, Uemura K, Takahashi R, Matsumoto N, Yamamoto T.
    • Journal Title

      J Hum Genet.

      Volume: Oct;61(10) Pages: 899-902

    • DOI

      10.1038/jhg.2016.64.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis.2016

    • Author(s)
      Shimojima K, Ondo Y, Matsufuji M, Sano N, Tsuru H, Oyoshi T, Higa N, Tokimura H, Arita K, Yamamoto T.
    • Journal Title

      Eur J Med Genet.

      Volume: 59(11) Pages: 559-563

    • DOI

      10.1016/j.ejmg.2016.10.006.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Novel SLC16A2 mutations in patients with Allan-Herndon-Dudley syndrome.2016

    • Author(s)
      Shimojima K, Maruyama K, Kikuchi M, Imai A, Inoue K, Yamamoto T.
    • Journal Title

      Intractable Rare Dis Res.

      Volume: 5(3) Pages: 214-217

    • DOI

      10.5582/irdr.2016.01051.

    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 7p22.1 microdeletions involving ACTB associated with developmental delay, short stature, and microcephaly.2016

    • Author(s)
      Shimojima K, Narai S, Togawa M, Doumoto T, Sangu N, Vanakker OM, de Paepe A, Edwards M, Whitehall J, Brescianini S, Petit F, Andrieux J, Yamamoto T.
    • Journal Title

      Eur J Med Genet.

      Volume: 59(10) Pages: 502-516

    • DOI

      10.1016/j.ejmg.2016.09.008.

    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] 多彩な合併症を示したMED13Lハプロ不全症候群の3例2016

    • Author(s)
      下島圭子、山本俊至、島川修、岡本伸彦
    • Organizer
      第39回日本小児遺伝学会学術集会
    • Place of Presentation
      慶應義塾大学三田キャンパス(東京都港区)
    • Year and Date
      2016-12-09 – 2016-12-10
  • [Presentation] ラムダ縫合早期癒合を示したMAP2K2領域の微細欠失によるRASopathies患者.2016

    • Author(s)
      下島圭子, 恩藤由美子, 松藤まゆみ, 佐野のぞみ, 水流尚志, 山本俊至.
    • Organizer
      第56回日本先天異常学会学術集会
    • Place of Presentation
      姫路商工会議所(兵庫県姫路市)
    • Year and Date
      2016-07-29 – 2016-07-31
  • [Presentation] 次世代シーケンスによるSNVスクリーニングだけではCNVが見逃される.2016

    • Author(s)
      山本俊至, 下島圭子, 恩藤由美子, 岡本伸彦.
    • Organizer
      第56回日本先天異常学会学術集会
    • Place of Presentation
      姫路商工会議所(兵庫県姫路市)
    • Year and Date
      2016-07-29 – 2016-07-31
  • [Presentation] Megalencephalic leukoencephalopathy with subcortical cystsの日本人8名におけるMLC1遺伝子解析.2016

    • Author(s)
      島田姿野, 山本俊至, 下島圭子, 永田智.
    • Organizer
      第58回日本小児神経学会学術集会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2016-06-03 – 2016-06-05
  • [Presentation] 非対称性大脳皮質異形成症症例に認められた新規TUBB3変異.2016

    • Author(s)
      下島圭子, 岡本伸彦, 山本俊至.
    • Organizer
      第58回日本小児神経学会学術集会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2016-06-03 – 2016-06-05
  • [Presentation] CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly.2016

    • Author(s)
      Shimojima K, Okumura A, Hayashi M, Kondo T, Inoue H, Yamamoto T.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Single nucleotide variation in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.2016

    • Author(s)
      Yamamoto T, Shimojima K, Komoike Y, Ishii A, Abe S, Yamashita S, Imai K, Kubota T, Fukasawa T, Okanishi T, Enoki H, Tanabe T, Saito A, Furukawa T, Shimizu T, Milligan CJ, Petrou S, Heron SE, Dibbens LM, Hirose S, Okumura A.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy.2016

    • Author(s)
      Yamamoto T, Shimojima K, Shibata T, Akiyama M, Oka M, Akiyama T, Yoshinaga H, Kobayashi K.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Mutation in the gene encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease.2016

    • Author(s)
      Shimada S, Shimojima K, Yamamoto T, Nagata S.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Tatton-Brown-Rahman syndrome due to 2p23 microdeletion.2016

    • Author(s)
      Ueda K, Okamoto N, Toribe Y, Shimojima K, Yamamoto T.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Novel mutation in the COL1A1 gene causes severe scoliosis and valvular heart disease in a Japanese family with osteogenesis imperfecta.2016

    • Author(s)
      Seto T, Yamamoto T, Shimojima K, Shintaku H.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Presentation] Two cases of monosomy of 3q with cerebral MRI findings.2016

    • Author(s)
      Dowa Y, Sameshima K, Ichinomiya K, Shiihara T, Shimojima K, Yamamoto T.
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      国立京都国際会館(京都府左京区)
    • Year and Date
      2016-04-03 – 2016-04-07
    • Int'l Joint Research
  • [Book] これならわかる!小児科診療に活かせる遺伝学的検査・診断・遺伝カウンセリングの上手な進めかた2016

    • Author(s)
      奥山虎之・山本俊至(編集)
    • Total Pages
      217
    • Publisher
      診断と治療社
  • [Book] iPS細胞の安全・高品質な作成技術2016

    • Author(s)
      下島圭子・山本俊至
    • Total Pages
      494
    • Publisher
      技術情報協会

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Published: 2018-01-16  

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