Identification of a novel childhood hematopoietic failure syndrome caused by combined mutations in ADH5 and ALDH2 that function in aldehyde metabolism.

• Project/Area Number: 16K15243
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Kyoto University
• Principal Investigator: HIRA Asuka 京都大学, 放射線生物研究センター, 研究員 (30772777)
• Co-Investigator(Renkei-kenkyūsha): SAITO Megumu 京都大学, iPS細胞研究所, 准教授 (90535486)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アルデヒド / ADH5 / ALDH2 / 小児骨髄不全 / ファンコニ貧血 / 骨髄不全 / フォルムアルデヒド

Outline of Final Research Achievements

Here we report a set of Japanese children (total six cases) with hypoplastic anemia and MDS who carried biallelic ADH5 gene mutations and monoallelic ALDH2*504Lys. Hematologically they were similar to FA but they displayed neither overt physical malformation nor increased levels of MMC-induced chromosome breakages.
To test the requirements of these genes for hematopoiesis in vitro, we destroyed these genes in human iPS cells derived from a healthy individual. The iPS cells lacking either ADH5 or ALDH2 showed normal in vitro differentiation potential into hematopoietic lineages, while drastic reduction was observed in ADH5-/-ALDH2+/- iPS cells. Furthermore, the patient derived iPS cells showed decreased colony numbers in clonogenic progenitor assay, which was reversed by exogenous expression of ADH5 or by treatment of cells with ALDH2 agonist drug Alda-1. These results prove the digenic origin of this disorder, and provide a potential therapeutic means for these patients.

Research Products

• [Journal Article] The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype. (2016)
  • Author(s): Yabe M, Yabe H, Morimoto T, Fukumura A, Ohtsubo K, Koike T, Yoshida K, Ogawa S, Ito E, Okuno Y, Muramatsu H, Kojima S, Matsuo K, Hira A, Takata M.
  • Journal Title: British Journal of Haematology Volume: 175 Pages: 457-461
  • DOI: 10.1111/bjh.14243
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Common variable immunodeficiency caused by FANC mutations. (2016)
  • Author(s): Yujin Sekinaka,Noriko Mitsuiki, Kohsuke Imai, Miharu Yabe, Hiromasa Yabe, Masatoshi Takagi, Ayako Arai, Kenichi Yoshida, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seiji Kojima, Asuka Hira, Minoru Takata, Osamu Ohara, Seishi Ogawa, Tomohiro Morio, and Shigeaki Nonoyama
  • Organizer: The 17th Biennial Meeting of the European Society for Immunodeficiencies (ESID 2016)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Myelodysplastic syndrome and acute myeloid leukemia in Japanese Fanconi anemia patients. (2016)
  • Author(s): Miharu Yabe, Tsuyoshi Morimoto, Akiko Fukumura, Keisuke Ohtsubo, Takashi Koike, Takashi Shimizu, Hiromitsu Takakura, Katsuyoshi Koh, Etsuro Ito, Seiji Kojima, Asuka Hira, Minoru Takata and Hiromasa Yabe.
  • Organizer: 28th Annual Fanconi Anemia research frund Scientific Symposium.
  • Place of Presentation: Bellevue, WA USA
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Book] 遺伝子医学MOOK別冊 シリーズ1, 最新遺伝性腫瘍・家族性腫瘍研究と遺伝カウンセリング (2016)
  • Author(s): 平 明日香、稲野 将二郎、髙田 穰
  • Total Pages: 328
  • Publisher: メディカルドゥ