International collaborative effort to study of pathophysiology and development of novel therapy of congenital sideroblastic anemia

• Project/Area Number: 17H04668
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 海外学術
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Harigae Hideo 東北大学, 医学系研究科, 教授 (50302146)
• Co-Investigator(Kenkyū-buntansha): 梨井 康 国立研究開発法人国立成育医療研究センター, 移植免疫研究室, 室長 (60321890)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 鉄芽球性貧血 / 血液内科学 / 内科

Outline of Final Research Achievements

As congenital sideroblastic anemia (CSA)is very rare, there is a need to collect the data of patients and clarify the molecular pathogenesis to develop a novel therapy by the international collaborative study. In this study, 17 cases of congenital sideroblastic anemia were found at Chinese Academy of Medical Sciences and Peking Union Medical College. In 7 out of 17cases, mutations of 5-aminolevulinate synthase (ALAS2) gene, which is the first enzyme of heme biosynthesis in erythroid cells were identified. In addition, mutations of SLC25A38 gene, which codes the mitochondrial glycine transporter were identified in 3 out of 17cases. Gene mutations of 22 congenital anemia cases at National Institute of Immunohaematology in India were analyzed; however, mutations responsible for CSA were not identified. In Japan, a novel mutation of HSPA9 gene and SLC5A6 gene was found. The significance of mutations are being confirmed by in vitro differentiation system established in this study.

Academic Significance and Societal Importance of the Research Achievements

遺伝性鉄芽球性貧血はミトコンドリアにおける鉄代謝に異常が生じ発症する難治性貧血である。極めてまれな疾患で、新たな治療法の開発には国際間での症例の蓄積が必要である。本研究によって、中国・インドにおいても症例数が限られていることが明らかとなった。一方で、中国で確認された症例の遺伝子変異は日本でのそれと類似していることが確認できた。また、本邦においても新たな候補遺伝子が確認され、本研究で確立したin vitroのモデル系で検証中である。本研究で国際的な共同研究体制が確立できたこと、またin vitroでのモデル系が確立できたことは極めて学術的・社会的に意義があると思われる。

Research Products

• [Int'l Joint Research] 湛江中心人民医院(中国)
• [Int'l Joint Research] ハーバード大学(米国)
• [Int'l Joint Research] 天津血液医院(中国)
• [Int'l Joint Research] ICMR(インド)
• [Journal Article] Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation. (2019)
  • Author(s): Saito K, Fujiwara T, Hatta S, Morita M, Ono K, Suzuki C, Fukuhara N, Onishi Y, Nakamura Y, Kawamata S, Shimizu R, Yamamoto M, Harigae H.
  • Journal Title: Mol Cell Biol Volume: 39
  • DOI: 10.1128/mcb.00387-18
  • Peer Reviewed
• [Journal Article] Iron as Soul of Life on Earth Revisited: From Chemical Reaction, Ferroptosis to Therapeutics (2019)
  • Author(s): Harigae Hideo、Hino Keisuke、Toyokuni Shinya
  • Journal Title: Free Radic Biol Med. Volume: 133 Pages: 1-2
  • DOI: 10.1016/j.freeradbiomed.2019.01.042
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Study of pathophysiology and molecular characterization of congenital anemia in India using targeted next-generation sequencing approach (2019)
  • Author(s): Kedar PS, Harigae H, Ito E, Muramatsu H, Kojima S, Okuno Y, Fujiwara T, Dongerdiye R, Warang PP, Madkaikar MR
  • Journal Title: Int J Hematol. Volume: 60 Pages: 408-416
  • DOI: 10.1007/s12185-019-02716-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia (2019)
  • Author(s): Fujiwara T, Harigae H
  • Journal Title: Free Radic Biol Med. Volume: 133 Pages: 179-185
  • DOI: 10.1016/j.freeradbiomed.2018.08.008
  • Peer Reviewed
• [Journal Article] Five-aminolevulinic acid: New Approach for Congenital Sideroblastic Anemia (2018)
  • Author(s): Ishida H, Imamura T, Morimoto A, Fujiwara T, Harigae H
  • Journal Title: Pediatr Int. Volume: 60 Pages: 496-497
  • DOI: 10.1111/ped.13558
  • Peer Reviewed
• [Journal Article] Successful treatment of X-linked sideroblastic anemia with <i>ALAS2</i> R452H mutation using vitamin B₆ (2018)
  • Author(s): Kawakami T, Nakazawa H, Kawakami F, Matsuzawa S, Sudo Y, Sakai H, Nishina S, Senoo N, Senoo Y, Komatsu M, Umemura T, Yamaguchi T, Kosho T, Fujiwara T, Harigae H, Ishida F.
  • Journal Title: Jpn. J. Clin. Hematol. Volume: 59 Issue: 4 Pages: 401-406
  • DOI: 10.11406/rinketsu.59.401
  • NAID: 130006733285
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] A defined culture method enabling the establishment of ring sideroblasts from induced pluripotent cells of X-linked sideroblastic anemia. (2018)
  • Author(s): 1.Hatta S, Fujiwara T, Yamamoto T, Saito K, Kamata M, Tamai Y, Kawamata S, Harigae H.
  • Journal Title: Haematologica Volume: - Pages: 188-191
  • DOI: 10.3324/haematol.2017.179770
  • Peer Reviewed / Open Access
• [Journal Article] A novel heterozygous ALAS2 mutation in a female with macrocytic sideroblastic anemia resembling myelodysplastic syndrome with ring sideroblasts: a case report and literature review (2017)
  • Author(s): Fujiwara T, Fukuhara N, Ichikawa S, Kobayashi M, Okitsu Y, Onishi Y, Furuyama K, Harigae H
  • Journal Title: Ann Hematol. Volume: 96(11) Pages: 1955-1957
  • DOI: 10.1007/s00277-017-3106-7
  • Peer Reviewed / Open Access
• [Journal Article] Dynamics of absorption, metabolism, and excretion of 5-aminolevulinic acid in human intestinal Caco-2 cells. (2017)
  • Author(s): Saito K, Fujiwara T, Ota U, Hatta S, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Ishizuka M, Tanaka T, Harigae H
  • Journal Title: Biochem Biophys Rep Volume: 11 Pages: 105-111
  • DOI: 10.1016/j.bbrep.2017.07.006
  • Peer Reviewed / Open Access
• [Presentation] CRISPR/Cas9を用いたALAS2ミスセンス変異導入によるX連鎖性鉄芽球性貧血のモデル細胞 (2019)
  • Author(s): 小野浩弥、高橋昇之、藤原亨、細川奈津子、齋藤慧、鈴木千恵、小野寺晃一、市川聡、福原規子、大西康、張替秀郎
  • Organizer: 第43回日本鉄バイオサイエンス学会学術集会
• [Presentation] HRM解析による簡易SF3B1遺伝子変異スクリーニング法の確立 (2019)
  • Author(s): 鈴木千恵、藤原亨、平泉敦子、藤巻慎一、張替秀郎
  • Organizer: 第43回日本鉄バイオサイエンス学会学術集会
• [Presentation] Establishment of cellular model of X-linked sideroblastic anemia using homology-directed CRISPR/Cas9 (2019)
  • Author(s): Koya Ono,Noriyuki Takahashi ,Toru Fujiwara,Kei Saito ,Koichi Onodera ,Satoshi Ichikawa ,Noriko Fukuhara ,Yasushi Onishi ,Hideo Harigae
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Role of mitochondrial membrane protein FAM210B during erythroid differentiation (2019)
  • Author(s): Chie Suzuki ,Toru Fujiwara ,Kei Saito,Hiroki Shima ,Koya Ono,Koichi Onodera,Satoshi Ichikawa ,Noriko Fukuhara ,Yasushi Onishi ,Yukio Nakamura,Hideo Harigae
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Molecular Characterization and Novel Therapeutic Strategy for X-Linked Sideroblastic (2019)
  • Author(s): Koya Ono, Tohru Fujiwara, Kei Saito, Chie Suzuki , Noriyuki Takahashi , Koichi
  • Organizer: 61 st ASH Annual Meeting & Exposition (第61回アメリカ血液学会）
  • Int'l Joint Research
• [Presentation] Proteomic Analysis of Mitochondrial Membrane Protein FAM210B in Erythroid Cells (2019)
  • Author(s): Chie Suzuki , Tohru Fujiwara, Hiroki Shima , Koya Ono, Kei Saito , Noriko Fukuhara,Yasushi Onishi, Hisayuki Yokoyama, Shinichi Fujimaki , Yukio Nakamura, Hideo Harigae,
  • Organizer: 61 st ASH Annual Meeting & Exposition (第61回アメリカ血液学会）
  • Int'l Joint Research
• [Presentation] X連鎖性鉄芽球性貧血モデルの樹立および特性解析 (2018)
  • Author(s): 斎藤慧、藤原亨、八田俊介、福原規子、大西康、中村幸夫、田中徹、張替秀郎
  • Organizer: 第42回日本鉄バイオサイエンス学会
• [Presentation] X連鎖性鉄芽球性貧血患者の疾患特異的iPS細胞の樹立 (2018)
  • Author(s): 藤原亨、八田俊介、斎藤慧、福原規子、大西康、田中徹、川真田伸、張替秀郎
  • Organizer: 第42回日本鉄バイオサイエンス学会
• [Presentation] 鉄代謝と貧血 (2018)
  • Author(s): 張替秀郎
  • Organizer: 日本内科学会
  • Invited
• [Presentation] Characterization of in vitro model of X-linked sideroblastic anemia (2018)
  • Author(s): Saito K, Fujiwara T, Hatta S, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Nakamura Y, Harigae H
  • Organizer: 第80回日本血液学会
• [Presentation] Generation and Molecular Characterization of Human Ring Sideroblasts (2018)
  • Author(s): Saito K, Fujiwara T, Hatta S, Suzuki C, Fukuhara N, Onishi Y, Nakamura Y, Harigae H
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Generation of induced pluripotent stem cell-derived erythroblasts of X-linked sideroblastic anemia (2017)
  • Author(s): Hatta S, Fujiwara T, Yamamoto T, Saito K, Kamata M, Tamai Y, Kawamata S, Harigae H
  • Organizer: 日本血液学会
• [Presentation] Establishment of in vivo and in vitro model of x-linked sideroblastic anemia by CRISPER/Cas9 (2017)
  • Author(s): Saito K, Fujiwara T, Morita M, Hatta S, Fukuhara N, Onishi Y, Nakamura n, Shimizu R, Harigae H
  • Organizer: 日本血液学会
• [Presentation] A novel therapeutic approach for congenital sideroblastic anemia using 5-aminolevulinic acid. (2017)
  • Author(s): Ishida H, Fujiki A. Imamura T, Morimoto A, Ota U, Takahashi K, Ishizawa M, Fujiwara T, Harigae H
  • Organizer: 日本血液学会
• [Presentation] ALAS2遺伝子変異を認めた大球性鉄芽球性貧血の一例 (2017)
  • Author(s): 藤原亨、福原規子、猪俣美津恵、大西康、古山和道、張替秀郎
  • Organizer: 日本鉄バイオサイエンス学会
• [Presentation] 鉄と赤血球造血 (2017)
  • Author(s): 張替秀郎
  • Organizer: 日本微量元素学会
• [Presentation] 鉄芽球性貧血の病態 (2017)
  • Author(s): 張替秀郎
  • Organizer: 臨床ストレス応答学会
• [Presentation] Establishment of in vivo and in vitro model of X-linked sideroblastic anemia (2017)
  • Author(s): Saito K, Fujiwara T, Morita M, Hatta S, Fukuhara N, Onishi Y, Nakamura Y, Shimizu R, Harigae H
  • Organizer: Congress of European Hematology Society
  • Int'l Joint Research
• [Presentation] Establishment of in vitro model of X-linked sideroblastic anemia (2017)
  • Author(s): Saito K, Fujiwara T, Hatta S, Oktsu Y, Fukuhara N, Onishi Y, Nakamura Y, Harigae H
  • Organizer: ASH Annual Meeting & Exposition
  • Int'l Joint Research