Identification of new responsible gene for chronic mucocutaneous candidiasis disease. Analysis of molecular pathogenesis of STAT1 dysregulation.

• Project/Area Number: 25713039
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Okada Satoshi 広島大学, 医歯薬保健学研究院(医), 講師 (80457241)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: RORγT / STAT1 / CMC / MSMD / アラニンスキャニング / CMCD / BCG / 機能獲得性変異 / カンジダ / 脱リン酸化障害

Outline of Final Research Achievements

We discovered bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγT resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+ CXCR3+ αβT cells. We thus discovered that both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγT in human （Okada S, et al. Science 349: 606-13, 2015).
We performed functional assay based on systematic alanine-scanning mutagenesis of human STAT1, which can be used to estimate the gain-of-function or loss-of-function status of nonsynonymous mutations (manuscript in preparation).

Research Products

• [Int'l Joint Research] The Rockefeller University/Boston Children's Hospital,/Trudeau Institute(米国)
• [Int'l Joint Research] INSERM/Necker Hospital for Sick Children/Imagine Institute(France)
• [Int'l Joint Research] Garvan Institute of Medical Research(オーストラリア)
• [Int'l Joint Research] Cardiff University/Royal Manchester Children's Hospital(United Kingdom)
• [Int'l Joint Research] Institute for Research in Biomedicine(Switzerland)
• [Int'l Joint Research]
• [Journal Article] A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. (2016)
  • Author(s): Hayakawa S, Okada S, Tsumura M, Sakata S, Ueno Y, Imai K, Morio T, Ohara O, Chayama K, Kobayashi M.
  • Journal Title: J. Clin. Immunol.. Volume: 36 Issue: 1 Pages: 28-32
  • DOI: 10.1007/s10875-015-0221-x
  • Peer Reviewed
• [Journal Article] 1)Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation (2016)
  • Author(s): Kataoka S, Muramatsu H, Okuno Y, Hayashi Y, Mizoguchi Y, Tsumura M, Okada S, Kobayashi M, Sano C, Sato H, Oh-Iwa I, Ito M, Kojima D Hama A, Takahashi Y, Kojima S
  • Journal Title: J Allergy Clin Immunol Volume: 137 Issue: 2 Pages: 619-622
  • DOI: 10.1016/j.jaci.2015.06.028
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impairment of IL-17A/F immunity to Candida and IFN-γ immunity to Mycobacterium in humans with inherited RORγT deficiency. (2015)
  • Author(s): Okada S, Markle JG, Deenick EK, Federico Mele F, Averbuch D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL
  • Journal Title: Science Volume: 349 Issue: 6248 Pages: 606-613
  • DOI: 10.1126/science.aaa4282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections. (2015)
  • Author(s): Dobbs K, Dominguez Conde C, Zhang SY, Parolini S, Audry M, Chou J, Haapaniemi E, Keles S, Bilic I, Okada S, et al.
  • Journal Title: N Engl J Med. Volume: 372 Issue: 25 Pages: 2409-22
  • DOI: 10.1056/nejmoa1413462
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. (2015)
  • Author(s): Kreins A.Y, Ciancanelli M.J, Boisson-Dupuis S, et al.
  • Journal Title: J Exp Med. Volume: 212 Issue: 10 Pages: 1641-1662
  • DOI: 10.1084/jem.20140280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. (2015)
  • Author(s): Ma CS, Wong N, Tangye SG, et al.
  • Journal Title: J Allergy Clin Immunol Volume: 136 Issue: 4 Pages: 993-1006
  • DOI: 10.1016/j.jaci.2015.05.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. (2015)
  • Author(s): Hirata O, Okada S, Ttsumura M, Karakawa S, Matsumura I, Kimura Y, Mihara T, Yasunaga S, Takihara Y, Ohara O, Kobayashi M
  • Journal Title: Journal of Clinical Immunology Volume: 2015 Issue: 5 Pages: 1-5
  • DOI: 10.1007/s10875-015-0165-1
  • Peer Reviewed / Open Access
• [Journal Article] DOCK2 and a Recessive Immunodeficiency with Early-Onset Invasive Infections. (2015)
  • Author(s): Dobbs K, Conde CD, Zhang SY, Parolini S, Audry M, Chou J, Haapaniemi E, Keles S, Bilic I, Okada S, et al.
  • Journal Title: N Engl J Med Volume: in press
  • Peer Reviewed
• [Journal Article] Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. (2015)
  • Author(s): Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, Volpi S, Li Z, Sanal O, Mansouri D, Tezcan I, Rice GI, Chen C, Mansouri N, Mahdaviani SA, Itan Y, Boisson B, Okada S, et al.
  • Journal Title: Nature Volume: 517 Issue: 7532 Pages: 667-76
  • DOI: 10.1038/nature13801
  • Peer Reviewed
• [Journal Article] Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency (2014)
  • Author(s): Ciancanelli MJ, Huang SX, Luthra, Garner H, Itan Y, Volpi S, Lafaille FG, Trouillet C, Schmolke M, Albrecht RA, Israelsson E, Lim HK, Casadio M, Hermesh T, Lorenzo L, Leung LW, Pedergnana V, Boisson B, Okada S, et al.
  • Journal Title: Science Volume: Epub Issue: 6233 Pages: 448-53
  • DOI: 10.1126/science.aaa1578
  • Peer Reviewed
• [Journal Article] A 2-year-old Japanese girl with TNF receptor-associated periodic syndrome: A case report of the youngest diagnosed proband in Japan. (2014)
  • Author(s): Yasumura J, Wago M, Okada S, et al.
  • Journal Title: Mod Rheumatol. Volume: 20 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J. Leukoc. Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1189/jlb.0513250
  • Peer Reviewed / Open Access
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J Leukoc Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1038/jid.2013.480
  • Peer Reviewed
• [Journal Article] New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. (2013)
  • Author(s): Soltesz B, Toth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, Abhyankar A, Csorba G, Tasko S, Sarkadi AK, Mehes L, Rozsival P, Neumann D, Chernyshova L, Tulassay Z, Puel A, Casanova JL, Sediva A, Litzman J, Marodi L.
  • Journal Title: J Med Genet. Volume: 50 Issue: 9 Pages: 567-78
  • DOI: 10.1136/jmedgenet-2013-101570
  • Peer Reviewed
• [Journal Article] Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis (2013)
  • Author(s): Hirata, O.
  • Journal Title: Haematologica Volume: 98 Issue: 10 Pages: 1641-1649
  • DOI: 10.3324/haematol.2013.083741
  • Peer Reviewed
• [Journal Article] Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation. (2013)
  • Author(s): Moncada-Velez M, Martinez-Barricarte R, Bogunovic D, Kong XF, Blancas-Galicia L, Tirpan C, Aksu G, Vincent QB, Boisson B, Itan Y, Ramirez-Alejo N, Okada S, et. al.
  • Journal Title: Blood Volume: 122 Issue: 14 Pages: 2390-401
  • DOI: 10.1182/blood-2013-01-480814
  • Peer Reviewed
• [Journal Article] A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. (2013)
  • Author(s): Kong XF, Bousfiha A, Rouissi A, Itan Y, Abhyankar A, Bryant V, Okada S, Ailal F, Bustamante J, Casanova JL, Hirst J, Boisson-Dupuis S.
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e58286-e58286
  • DOI: 10.1371/journal.pone.0058286
  • Peer Reviewed
• [Journal Article] Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. (2013)
  • Author(s): Grant AV, El Baghdadi J, Sabri A, El Azbaoui S, Alaoui-Tahiri K, Abderrahmani Rhorfi I, Gharbaoui Y, Abid A, Benkirane M, Raharimanga V, Richard V, Orlova M, Boland A, Migaud M, Okada S, et al.
  • Journal Title: Am J Hum Genet. Volume: 92 Issue: 3 Pages: 407-14
  • DOI: 10.1016/j.ajhg.2013.01.013
  • Peer Reviewed
• [Presentation] Impairment of IL-17 immunity to Candida and IFN-γ immunity to Mycobacterium in humans with inherited RORγT deficiency (2015)
  • Author(s): Satoshi Okada, Janet Markle, Anne Puel, Jacinta Bustamante, Masao Kobayashi, and Jean-Laurent Casanova
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Sapporo
  • Year and Date: 2015-11-18
• [Presentation] RORγT 異常による原発性免疫不全症 (2015)
  • Author(s): 岡田 賢, 小林正夫
  • Organizer: 日本人類遺伝学会 第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-15
• [Presentation] Chronic Mucocutaneous Candidiasis (2015)
  • Author(s): Satoshi Okada
  • Organizer: Pediatric Academic Societies annual meeting 2015
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2015-04-26
  • Int'l Joint Research / Invited
• [Presentation] 慢性皮膚粘膜カンジダ症 ～IL-17異常を分子基盤とした原発性免疫不全症～ (2015)
  • Author(s): 岡田 賢
  • Organizer: 第25回 日本小児リウマチ学会 総会・学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-04-26
  • Invited
• [Presentation] Chronic Mucocutaneous Candidiasis (2015)
  • Author(s): Okada S
  • Organizer: Pediatric Academic Society annual meeting 2015
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-04-25 – 2015-04-28
• [Presentation] 新生児期の好中球減少症 (2014)
  • Author(s): 岡田 賢, 中村和洋, 小林正夫
  • Organizer: 第2回 日本産婦人科・新生児血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-06-13 – 2014-06-14
  • Invited
• [Presentation] 新生児期の好中球減少症 (2014)
  • Author(s): 岡田 賢
  • Organizer: 日本産婦人科・新生児血液学会学術集会
  • Place of Presentation: 横浜
• [Presentation] STAT1異常による原発性免疫不全症 (2013)
  • Author(s): 岡田 賢
  • Organizer: 日本小児科学会
  • Place of Presentation: 広島
• [Book] STAT1 gain-of-function mutation, 免疫不全症候群（第２版）III (2016)
  • Author(s): 岡田 賢
  • Publisher: 日本臨症社
• [Book] IL-17F異常症, 免疫不全症候群（第２版）III (2016)
  • Author(s): 香川礼子, 岡田 賢
  • Publisher: 日本臨症社
• [Book] IL-17RA欠損症, 免疫不全症候群（第２版）III (2016)
  • Author(s): 浅野孝基, 岡田 賢
  • Publisher: 日本臨症社
• [Book] CARD9欠損症, 免疫不全症候群（第２版）III (2016)
  • Author(s): 早川誠一, 岡田 賢
  • Publisher: 日本臨症社
• [Book] ACT1異常症, 免疫不全症候群（第２版）III (2016)
  • Author(s): 坂田園子, 岡田 賢
  • Publisher: 日本臨症社
• [Book] 慢性皮膚粘膜カンジダ症, 小児疾患診療のための病態生理2 改訂第5版 (2015)
  • Author(s): 岡田 賢, 小林正夫
  • Publisher: 東京医学社
• [Book] MSMD, 小児疾患診療のための病態生理2 改訂第5版 (2015)
  • Author(s): 岡田 賢, 小林正夫
  • Publisher: 東京医学社
• [Book] 好中球減少症および白血球接着異常症, 小児疾患診療のための病態生理2 改訂第5版 (2015)
  • Author(s): 溝口洋子, 小林正夫, 岡田 賢
  • Publisher: 東京医学社
• [Remarks] [研究成果]慢性皮膚粘膜カンジダ感染とマイコバクテリア感染が同時に起こる原因遺伝子を同定
  • URL: http://www.hiroshima-u.ac.jp/news/show/id/23584
• [Remarks] 世界初！ヒトにおいてRORC遺伝子異常が原発性免疫不全症の原因になることを同定
  • URL: http://www.hiroshima-u.ac.jp/top/kenkyu/now/no42/
• [Remarks] Candida属細菌に対する粘膜免疫およびMycobacterium属細菌に対する全身性の免疫応答
  • URL: http://first.lifesciencedb.jp/archives/10513