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Defects in histone modification cause phenotypic diversity of congenital malformations

Research Project

Project/Area Number 20K08270
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionKanagawa Children's Medical Center (Clinical Research Institute)

Principal Investigator

Kurosawa Kenji  地方独立行政法人神奈川県立病院機構神奈川県立こども医療センター(臨床研究所), 臨床研究所, 臨床研究所長 (20277031)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsヒストン / エピゲノム / 先天異常 / クロマチン / 次世代シーケンサー / ゲノム / Acetyltransferase / 知的障害 / AGO1 / KAT6B / てんかん / 自閉スペクトラム症 / SET / CREBBP / マイクロアレイ / トランスクリプトーム / エクソーム
Outline of Research at the Start

ヒトのエピゲノム修飾の先天的傷害は、さまざまな先天異常疾患および自閉症スペクトラムをもたらす。特にヒストン修飾、クロマチンリモデリング異常は、多臓器にわたる特徴的な症状を呈する。しかし、この疾患群の多様性と共通性の原因は明らかにされていない。一方で、ヒト先天異常疾患との関連が明らかにされていないヒストン修飾因子やクロマチンリモデリング複合体構成因子もある。本研究では、多臓器障害をもつ先天異常疾患症例を対象に、詳細な臨床情報を集積しつつ、網羅的ゲノム解析およびトランスクリプトーム解析を用いて、新規の先天性エピゲノム修飾異常症の同定を試み、その治療戦略の基盤を確立する。

Outline of Final Research Achievements

We studied histone modification defects to uncover the mechanisms behind diverse congenital malformation syndromes. We have identified a novel variant in the atypical region associated with Say-Barber-Biesecker-Young-Simpson syndrome, which has led to the development of autism spectrum disorder. Through our investigation of a microdeletion involving the SET gene, which encodes the SET nuclear proto-oncogene, we have identified a new cranial formation phenotype. Additionally, we have established a link between the phenotype and genotype in Rubinstein-Taybi syndrome caused by the acetyltransferase CREBBP. These findings suggest that the various clinical symptoms resulting from abnormalities in histone modifications stem not only from different genetic variations but also from the diverse functions of individual histone modifiers by domain. Further analysis is needed to explore potential therapeutic approaches.

Academic Significance and Societal Importance of the Research Achievements

先天異常症候群において、ヒストン修飾因子およびその関連因子の異常を原因とする疾患は少なくない。多くは、根本治療は困難で対症療法が中心となる。治療への手がかりとして発症メカニズムの解明は重要である。今回の研究により、表現型(臨床像)の多様性が変異の多様性に由来し、同じ因子であっても変異の種類によって発症機構が大きく異なることを明らかにできた。このことは、社会的には患者家族に疾患理解を促すこととなり、学術的には治療法開発の手がかりとなりえる。

Report

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

    (35 results)

All 2024 2023 2022 2021 2020

All Journal Article (17 results) (of which Peer Reviewed: 12 results,  Open Access: 6 results) Presentation (18 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results)

  • [Journal Article] マイクロアレイ染色体検査の原理と臨床応用2024

    • Author(s)
      黒澤健司
    • Journal Title

      新生児成育医学会雑誌

      Volume: 36

    • Related Report
      2023 Annual Research Report
  • [Journal Article] 遺伝学的検査の保険収載2023

    • Author(s)
      黒澤健司
    • Journal Title

      遺伝子医学

      Volume: 13 Pages: 23-32

    • Related Report
      2023 Annual Research Report
  • [Journal Article] 先天異常症候群2023

    • Author(s)
      黒澤健司
    • Journal Title

      小児科臨床

      Volume: 76 Pages: 193-196

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Delineation of a Phenotype Caused by a KAT6B Missense Variant Not Resembling Say-Barber-Biesecker-Young-Simpson and Genitopatellar Syndromes.2022

    • Author(s)
      Nishimura Naoto、Enomoto Yumi、Kumaki Tatsuro、Murakami Hiroaki、Ikeda Azusa、Goto Tomohide、Kurosawa Kenji
    • Journal Title

      Molecular Syndromology

      Volume: 13 Issue: 3 Pages: 221-225

    • DOI

      10.1159/000520134

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel COL2A1 variants in Japanese patients with spondyloepiphyseal dysplasia congenita2022

    • Author(s)
      Akahira-Azuma Moe、Enomoto Yumi、Nakamura Naoyuki、Yokoi Takayuki、Minatogawa Mari、Harada Noriaki、Tsurusaki Yoshinori、Kurosawa Kenji
    • Journal Title

      Human Genome Variation

      Volume: 9 Issue: 1 Pages: 16-16

    • DOI

      10.1038/s41439-022-00193-x

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mosaicism of a Truncating Variant of CASK Causes Congenital Heart Disease and Neurodevelopmental Disorder2022

    • Author(s)
      Abe-Hatano Chihiro、Yokoi Takayuki、Ida Kazumi、Kurosawa Kenji
    • Journal Title

      Molecular Syndromology

      Volume: 13 Issue: 6 Pages: 517-521

    • DOI

      10.1159/000524375

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Complex congenital cardiovascular anomaly in a patient with AGO1‐associated disorder2022

    • Author(s)
      Takagi Minako、Ono Shin、Kumaki Tatsuro、Nishimura Naoto、Murakami Hiroaki、Enomoto Yumi、Naruto Takuya、Ueda Hideaki、Kurosawa Kenji
    • Journal Title

      American Journal of Medical Genetics Part A

      Volume: 191 Issue: 3 Pages: 882-892

    • DOI

      10.1002/ajmg.a.63089

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ヤング・シンプソン症候群2022

    • Author(s)
      黒澤健司
    • Journal Title

      遺伝子医学

      Volume: 12 Pages: 85-89

    • Related Report
      2022 Research-status Report
  • [Journal Article] Down症候群・その他の先天異常症候群2022

    • Author(s)
      黒澤健司
    • Journal Title

      小児内科

      Volume: 54 Pages: 1635-1638

    • Related Report
      2022 Research-status Report
  • [Journal Article] Further delineation of <scp> <i>SET</i> </scp> ‐related intellectual disability syndrome2022

    • Author(s)
      Shono Kenta、Enomoto Yumi、Tsurusaki Yoshinori、Kumaki Tatsuro、Masuno Mitsuo、Kurosawa Kenji
    • Journal Title

      American Journal of Medical Genetics Part A

      Volume: 188 Issue: 5 Pages: 1595-1599

    • DOI

      10.1002/ajmg.a.62681

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Divergent variant patterns among 19 patients with Rubinstein-Taybi syndrome uncovered by comprehensive genetic analysis including whole genome sequencing2022

    • Author(s)
      Enomoto Y, Yokoi T, Tsurusaki Y, Murakami H, Tominaga M, Minatogawa M, Abe-Hatano C, Kuroda Y, Ohashi I, Ida K, Shiiya S, Kumaki T, Naruto T, Mitsui J, Harada N, Kido Y, Kurosawa K
    • Journal Title

      Clinical Genetics

      Volume: 101 Issue: 3 Pages: 335-345

    • DOI

      10.1111/cge.14103

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Persistent Hyperplastic Primary Vitreous with Microphthalmia and Coloboma in a Patient with Okur-Chung Neurodevelopmental Syndrome2021

    • Author(s)
      Murakami Hiroaki、Uehara Tomoko、Enomoto Yumi、Nishimura Naoto、Kumaki Tatsuro、Kuroda Yukiko、Asano Mizuki、Aida Noriko、Kosaki Kenjiro、Kurosawa Kenji
    • Journal Title

      Molecular Syndromology

      Volume: 13 Issue: 1 Pages: 75-79

    • DOI

      10.1159/000517977

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Progression of cerebral and cerebellar atrophy in congenital contractures of limbs and face, hypotonia, and developmental delay2021

    • Author(s)
      Kumaki Tatsuro、Enomoto Yumi、Aida Noriko、Goto Tomohide、Kurosawa Kenji
    • Journal Title

      Pediatrics International

      Volume: 64 Issue: 1

    • DOI

      10.1111/ped.14734

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] 6p21.33 Deletion encompassing CSNK2B is associated with relative macrocephaly, facial dysmorphism, and mild intellectual disability2021

    • Author(s)
      Ohashi Ikuko、Kuroda Yukiko、Enomoto Yumi、Murakami Hiroaki、Masuno Mitsuo、Kurosawa Kenji
    • Journal Title

      Clinical Dysmorphology

      Volume: 30 Issue: 3 Pages: 139-141

    • DOI

      10.1097/mcd.0000000000000372

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Lung disease due to FLNA mutation improved after shunt closure for congenital heart disease2021

    • Author(s)
      Mori Satomi、Tanoue Koji、Shimizu Hiroyuki、Nagafuchi Hiroyuki、Kim Ki‐Sung、Murakami Hiroaki、Kurosawa Kenji、Matsui Kiyoshi
    • Journal Title

      Pediatric Pulmonology

      Volume: 56 Issue: 5 Pages: 1280-1282

    • DOI

      10.1002/ppul.25269

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Recurrent Variant in POLR1B, c.3007C>T; p.Arg1003Cys, Associated with Atresia of the External Canal and Microtia in Treacher Collins Syndrome Type 42021

    • Author(s)
      Enomoto Yumi、Tsurusaki Yoshinori、Tominaga Makiko、Kobayashi Shinji、Inoue Maki、Fujita Kazutoshi、Kumaki Tatsuro、Murakami Hiroaki、Kurosawa Kenji
    • Journal Title

      Molecular Syndromology

      Volume: - Issue: 2 Pages: 1-6

    • DOI

      10.1159/000513224

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Arthrogryposis multiplex congenita with polymicrogyria and infantile encephalopathy caused by a novel GRIN1 variant2020

    • Author(s)
      Nishimura Naoto、Kumaki Tatsuro、Murakami Hiroaki、Enomoto Yumi、Katsumata Kaoru、Toyoshima Katsuaki、Kurosawa Kenji
    • Journal Title

      Human Genome Variation

      Volume: 7 Issue: 1

    • DOI

      10.1038/s41439-020-00116-8

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Cerebral vasculopathy in Rubinstein-Taybi syndrome.2023

    • Author(s)
      Kurosawa K, Saito Y, Kuroda Y.
    • Organizer
      American Society of Human Genetics 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 保険収載された遺伝学的検査2023

    • Author(s)
      黒澤健司
    • Organizer
      第126回日本小児科学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 先天異常症候群の診かた考え方(マイクロアレイ染色体検査を手掛かりに)2023

    • Author(s)
      黒澤健司
    • Organizer
      第56回日本小児内分泌学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 難病の遺伝学的検査2023

    • Author(s)
      黒澤健司
    • Organizer
      第65回日本小児神経学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] マイクロアレイ染色体検査の臨床応用の実際2022

    • Author(s)
      黒澤健司
    • Organizer
      第125回日本小児科学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 小児神経科医が知っておきたい臨床遺伝学ABC2022

    • Author(s)
      黒澤健司
    • Organizer
      第64回日本小児神経学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 難病領域の遺伝学的検査-現状と課題2022

    • Author(s)
      黒澤健司
    • Organizer
      第29回日本遺伝子診療学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 先天異常の診かた考え方と診断アプローチとしての遺伝学的検査2022

    • Author(s)
      黒澤健司
    • Organizer
      第21回Haemostasis研究会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] マイクロアレイ染色体検査の医療実装と展望2022

    • Author(s)
      黒澤健司
    • Organizer
      第67回日本人類遺伝学会
    • Related Report
      2022 Research-status Report
  • [Presentation] 難病遺伝医療における保険診療の道のりと課題2022

    • Author(s)
      黒澤健司
    • Organizer
      第67回日本人類遺伝学会
    • Related Report
      2022 Research-status Report
  • [Presentation] ABL1のrecurrent変異による両側無眼球症の症例2021

    • Author(s)
      榎本友美、鶴﨑美徳、黒澤健司
    • Organizer
      第61回日本先天異常学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] SETおよびSPTAN1を含む9q34.11欠失症候群は知的障害と特徴的顔貌を示す2021

    • Author(s)
      黒澤健司、榎本友美、鶴﨑美徳
    • Organizer
      第61回日本先天異常学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] LARS1遺伝子異常の1例2021

    • Author(s)
      上原健史、関衛順、露崎悠、榎本友美、黒澤健司
    • Organizer
      第61回日本先天異常学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] LMX1B遺伝子変異を低頻度モザイクで持つ無症状の父親を由来として発症したNail-Patella syndromeの1例2021

    • Author(s)
      上原健史、関衛順、小澤南、榎本友美、黒澤健司
    • Organizer
      第66回日本人類遺伝学会
    • Related Report
      2021 Research-status Report
  • [Presentation] CREBBP/EP300の最終エクソンにミスセンス変異を同定したMenke-Hennekam症候群の2症例2021

    • Author(s)
      榎本友美、鶴崎美徳、熊木達郎、上原健史、黒澤健司
    • Organizer
      第66回日本人類遺伝学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 4p16.3微細欠失の遺伝子型と表現型の相関性に関する検討2020

    • Author(s)
      西村直人, 熊木達郎, 村上博昭, 黒澤健司
    • Organizer
      第123回日本小児科学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 難病の遺伝学的検査の体制2020

    • Author(s)
      黒澤健司
    • Organizer
      第27回日本遺伝子診療学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 先天異常の診かたと考え方2020

    • Author(s)
      黒澤健司
    • Organizer
      第29回日本形成外科学会基礎学術集会
    • Related Report
      2020 Research-status Report
    • Invited

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

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