The identification of the novel gene mutation and development of the novel therapy for dyskeratosis congenita

• Project/Area Number: 16K09832
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Nippon Medical School
• Principal Investigator: Yamaguchi Hiroki 日本医科大学, 医学部, 准教授 (90297937)
• Co-Investigator(Kenkyū-buntansha): 猪口 孝一 日本医科大学, 大学院医学研究科, 大学院教授 (10203267) ; 三宅 弘一 日本医科大学, 医学部, 准教授 (90267211)
• Research Collaborator: Terada Kazuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 先天性角化不全症 / テロメア制御遺伝子異常 / テロメラーゼ活性 / 新規遺伝子変異 / ACD遺伝子 / TINF2遺伝子 / TEP1遺伝子 / TEP1 / ACD / DNAヘリカーゼ遺伝子 / 遺伝子変異 / 遺伝子 / テロメア

Outline of Final Research Achievements

Telomerase activity in TERT carrying mutations detected in DKC patients (p.E280K or p.S334del) did not significantly differ from that in wild-type TERT. This makes it doubtful that the TERT mutations identified in DKC patients are causative for DKC. Next, we conducted a comprehensive analysis for DKC without the known gene mutation, and detected novel TEP1 mutations and ACD mutations. However, this ACD mutation did not cause binding inhibition of ACD and TINF2, and shelterin complexes destabilizes. The detected ACD mutation was not a responsibility in DKC.

Academic Significance and Societal Importance of the Research Achievements

DKCは重症型と考えられるHoyeraal Hreidarsson syndrome (HHS) から軽症型の不全型DKCまでその病態や臨床像が多彩である。変異解析技術が発展したため遺伝子変異検索によって診断が明確となった症例も多くある。一方で遺伝子変異の結果をどのように判断すればよいのか判断が難しい症例もある。またDKCの約1/3の症例では責任遺伝子変異が同定されていないため遺伝子診断が出来ない場合もある。今回の研究成果で症例によっては遺伝子変異のみでDKCを診断するのは難しいことが明らかになった。

Research Products

• [Journal Article] Fatal Acute Exacerbation of Familial Interstitial Pneumonia Complicated with Dyskeratosis Congenita after Influenza Virus B Infection. (2019)
  • Author(s): Tachiwada T, Oda K, Tahara M, Sennari K, Nemoto K, Noguchi S, Kawanami T, Kido T, Yamaguchi H, Yatera K.
  • Journal Title: Inter Med. Volume: 印刷中
  • NAID: 130007706914
  • Peer Reviewed
• [Journal Article] Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. (2017)
  • Author(s): Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Takahashi Y, Kanno H, Yamaguchi H, Ohga S, Manabe A, Harigae H, Kunishima S, Ishii E, Kobayashi M, Koike K, Watanabe K, Ito E, Takata M, Yabe M, Ogawa S, Miyano S, Kojima S.
  • Journal Title: Genet Med. Volume: - Issue: 7 Pages: 796-802
  • DOI: 10.1038/gim.2016.197
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 骨髄不全症におけるテロメア制御異常 (2017)
  • Author(s): 山口博樹
  • Journal Title: 血液フロンティア Volume: 27 Pages: 5-9
• [Journal Article] Hoyeraal-Hreidarsson syndrome in a patient with novel compound heterozygous RTEL1 gene mutations. (2016)
  • Author(s): Moriya K, Suzuki T, Watanabe Y, Saito-Nanjo Y, Niizuma H, Onuma M, Rikiishi T, Kakuta F, Abukawa D, Yamaguchi H, Sasahara1 Y, Kure S.
  • Journal Title: Pediatric Blood &Cancer. Volume: 63 Issue: 9 Pages: 1683-1684
  • DOI: 10.1002/pbc.26030
  • Peer Reviewed
• [Presentation] DKCの診断におけるTERT遺伝子変異の機能解析の重要性 (2017)
  • Author(s): Kazuki Terada, Hiroki Yamaguchi, Koichi Miyake, Noriko Miyake, Yoshiki Osaki, Takashi Okada, Seiji Kojima, Etsuro Ito, Koiti Inokuchi.
  • Organizer: 第79回日本血液学会学術集会
• [Book] 先天性骨髄不全症診療ガイドライン2017 (2017)
  • Author(s): 日本小児血液・がん学会
  • Total Pages: 77
  • Publisher: 診断と治療社