DNA double strand break repair defects and impaired immune and neuron cell differentiations in patients with EAOH caused by APTX mutation.

• Project/Area Number: 15K15396
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: National Defense Medical College
• Principal Investigator: Nonoyama Shgeaki 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 小児科学, 教授 (40280961)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 小児免疫 / アレルギー / 膠原病学

Outline of Final Research Achievements

Immunological analysis was performed on nine patients with early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH). Reduction of naive T cells and B cells, decrease of TREC, a marker of T cell neogenesis, and decrease of KREC, a marker of B cell neogenesis,,were observed in patients with EAOH. These results indicate that DNA double - strand break repair defects, in addition to DNA single - strand break repair defects, occur due to the mutations of APTX , which is a causative gene of EAOH. T cell and B cell developments were impaired in addition to nerve cells in EAOH.

Research Products

• [Journal Article] Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint. (2016)
  • Author(s): Cantaert T, Schickel J, Bannock, Ng Y, Massad C, Delmotte F, Yamakawa N, Glauzy S, Chamberlain N, Kinnunen T, Menard L, Lavoie A, Walter J, Notarangelo L, Bruneau J, Al-Herz W, Kilic S, Ochs H, Cunningham-Rundles C, Burg M, Kuijpers T, Kracker S, Kaneko H, Sekinaka Y, Nonoyama S, Durandy A, and Meffre E.
  • Journal Title: J Clin Invest. Volume: 126 Issue: 11 Pages: 4289-4302
  • DOI: 10.1172/jci84645
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. (2016)
  • Author(s): Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, Espinosa Rosales FJ, Hammarström L, Nonoyama S, Quinti I, Routes JM, Tang ML, Warnatz K.
  • Journal Title: J Allergy Clin Immunol Pract. Volume: 4 Issue: 1 Pages: 38-59
  • DOI: 10.1016/j.jaip.2015.07.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PTEN mutation can cause Activated PI3 Kinase Delta Syndrome (APDS)-like immunodeficiency. (2016)
  • Author(s): Tsujita Y, Mitsui-Sekinaka K, et al.
  • Journal Title: J Allergy Clin Immunol Volume: -
  • Peer Reviewed
• [Journal Article] Hematopoietic Stem Cell Transplantation for X-Linked Thrombocytopenia With Mutations in the WAS gene. (2015)
  • Author(s): Oshima K, Imai K, Albert M.H, Bittner T.C, Strauss G, Filipovich A.H, Morio T, Kapoor N, Dalal J, Schultz K.R, Casper J.T, Notarangelo L.D, Ochs H.D, Nonoyama S.
  • Journal Title: J Clin Immunol Volume: 35 Issue: 1 Pages: 15-21
  • DOI: 10.1007/s10875-014-0105-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RAG1 Deficiency May Present Clinically as Selective IgA Deficiency. (2015)
  • Author(s): Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, Nishida N, Kanegane H, Wada T, Yachie A, Ohara O, Morio T, Notarangelo LD, Imai K, Nonoyama S.
  • Journal Title: J Clin Immunol. Volume: 35(3) Issue: 3 Pages: 280-8
  • DOI: 10.1007/s10875-015-0146-4
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features and hematopoietic stem cell transplantation for CD40 ligand deficiency in Japan (2015)
  • Author(s): Mitsui-Sekinaka K, Imai K, Sato H, Tomizawa D, Kajiwara M, Nagasawa M, Morio T, Nonoyama S
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 4 Pages: 1018-1024
  • DOI: 10.1016/j.jaci.2015.02.020
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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] Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. (2015)
  • Author(s): Cantaert T, Schickel JN, Bannock JM, Ng YS, Massad C, Oe T, Wu R, Lavoie A, Walter JE, Notarangelo LD, Al-Herz W, Kilic SS, Ochs HD, Nonoyama S, Durandy A, Meffre E.
  • Journal Title: Immunity Volume: 17; 43 Issue: 5 Pages: 884-95
  • DOI: 10.1016/j.immuni.2015.10.002
  • Peer Reviewed / Int'l Joint Research