Skip to main content

Advertisement

SpringerLink
Log in

Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Mutations in Recombination Activating Genes (RAG1 and RAG2) are common genetic causes of severe combined immunodeficiency (SCID) and Omenn syndrome (OS). The clinical, immunologic, and genetic characteristics of RAG mutations in Chinese patients with SCID or OS have not been studied in detail. In this research, 22 RAG mutations were identified in 15 Chinese patients, including 10 novel mutations in RAG1 (R108X, M630T, E510X, S666P, E669K, C730Y, A857V, K847E, L922PfsX7, and L1025FfsX39) and 4 in RAG2 (R73C, I427GfsX12, P432L, and 311insL). L1025FfsX39 is a potential RAG1 hot-spot mutation in the Chinese population. The distribution of RAG1 mutations rather than mutation type seemed to differ between SCID and OS patients. The thymic output of T lymphocytes, TCR rearrangement, and T cell proliferation were severely impaired in RAG mutant patients. These findings will contribute to the early diagnosis and treatment of SCID and OS to a certain extent.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cirillo E, Giardino G, Gallo V, D’Assante R, Grasso F, Romano R, et al. Severe combined immunodeficiency-an update. Ann N Y Acad Sci. 2015. doi:10.1111/nyas.12849.

    PubMed  Google Scholar 

  2. Bogaert D, Van Schil K, Taghon T, Bordon V, Bonroy C, Dullaers M, et al. Persistent rotavirus diarrhea post-transplant in a novel JAK3-SCID patient after vaccination. Pediatr Allergy Immunol. 2015. doi:10.1111/pai.12455.

    PubMed  Google Scholar 

  3. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, et al. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell. 1995;83(3):387–95.

    Article  CAS  PubMed  Google Scholar 

  4. Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248(4962):1517–23.

    Article  CAS  PubMed  Google Scholar 

  5. van Gent DC, Ramsden DA, Gellert M. The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. Cell. 1996;85(1):107–13.

    Article  PubMed  Google Scholar 

  6. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97–9.

    Article  CAS  PubMed  Google Scholar 

  7. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93(5):885–96.

    Article  CAS  PubMed  Google Scholar 

  8. Kato M, Kimura H, Seki M, Shimada A, Hayashi Y, Morio T, et al. Omenn syndrome—review of several phenotypes of Omenn syndrome and RAG1/RAG2 mutations in Japan. Allergol Int. 2006;55(2):115–9. doi:10.2332/allergolint.55.115.

    Article  CAS  PubMed  Google Scholar 

  9. Niehues T, Perez-Becker R, Schuetz C. More than just SCID–the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin. Immunol. 2010;135(2):183–92. doi:10.1016/j.clim.2010.01.013.

    Article  CAS  PubMed  Google Scholar 

  10. Kuijpers TW, Ijspeert H, van Leeuwen EM, Jansen MH, Hazenberg MD, Weijer KC, et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood. 2011;117(22):5892–6. doi:10.1182/blood-2011-01-329052.

    Article  CAS  PubMed  Google Scholar 

  11. Ij H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K, et al. Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J Allergy Clin Immunol. 2014;133(4):1124–33. doi:10.1016/j.jaci.2013.11.028.

    Article  Google Scholar 

  12. Zhang ZY, Zhao XD, Jiang LP, Liu EM, Cui YX, Wang M, et al. Clinical characteristics and molecular analysis of three Chinese children with Omenn syndrome. Pediatr Allergy Immunol. 2011;22(5):482–7. doi:10.1111/j.1399-3038.2010.01126.x.

    Article  PubMed  Google Scholar 

  13. Lee PP, Chan KW, Chen TX, Jiang LP, Wang XC, Zeng HS, et al. Molecular diagnosis of severe combined immunodeficiency–identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children. J Clin Immunol. 2011;31(2):281–96. doi:10.1007/s10875-010-9489-z.

    Article  CAS  PubMed  Google Scholar 

  14. Ryu KH, Cho KA, Park HS, Kim JY, Woo SY, Jo I, et al. Tonsil-derived mesenchymal stromal cells: evaluation of biologic, immunologic and genetic factors for successful banking. Cytotherapy. 2012;14(10):1193–202. doi:10.3109/14653249.2012.706708.

    Article  CAS  PubMed  Google Scholar 

  15. Wu J, Liu D, Tu W, Song W, Zhao X. T-cell receptor diversity is selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015;135(1):209–16. doi:10.1016/j.jaci.2014.06.025.

    Article  CAS  PubMed  Google Scholar 

  16. Dion ML, Sekaly RP, Cheynier R. Estimating thymic function through quantification of T-cell receptor excision circles. Methods Mol Biol. 2007;380:197–213. doi:10.1007/978-1-59745-395-0_12.

    Article  CAS  PubMed  Google Scholar 

  17. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. doi:10.1016/j.immuni.2009.03.019.

    Article  CAS  PubMed  Google Scholar 

  18. Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–8. doi:10.1016/j.jaci.2013.09.044.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  20. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, Le Deist FL, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001;97(9):2772–6.

    Article  CAS  PubMed  Google Scholar 

  21. Ji Y, Little AJ, Banerjee JK, Hao B, Oltz EM, Krangel MS, et al. Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination. J Exp Med. 2010;207(13):2809–16. doi:10.1084/jem.20101136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jung D, Giallourakis C, Mostoslavsky R, Alt FW. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol. 2006;24:541–70. doi:10.1146/annurev.immunol.23.021704.115830.

    Article  CAS  PubMed  Google Scholar 

  23. Couedel C, Roman C, Jones A, Vezzoni P, Villa A, Cortes P. Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. J Clin Investig. 2010;120(4):1337–44. doi:10.1172/JCI41305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kwan A, Church JA, Cowan MJ, Agarwal R, Kapoor N, Kohn DB, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol. 2013;132(1):140–50. doi:10.1016/j.jaci.2013.04.024.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Borte S, von Dobeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552–5. doi:10.1182/blood-2011-08-371021.

    Article  CAS  PubMed  Google Scholar 

  26. Kim MS, Lapkouski M, Yang W, Gellert M. Crystal structure of the V(D)J recombinase RAG1–RAG2. Nature. 2015;518(7540):507–11. doi:10.1038/nature14174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sadeghi-Shabestari M, Vesal S, Jabbarpour-Bonyadi M, de Villatay JP, Fischer A, Rezaei N. Novel RAG2 mutation in a patient with T- B- severe combined immunodeficiency and disseminated BCG disease. J Investig Allergol Clin Immunol. 2009;19(6):494–6.

    CAS  PubMed  Google Scholar 

  28. Yeganeh M, Heidarzade M, Pourpak Z, Parvaneh N, Rezaei N, Gharagozlou M, et al. Severe combined immunodeficiency: a cohort of 40 patients. Pediatr Allergy Immunol. 2008;19(4):303–6. doi:10.1111/j.1399-3038.2007.00647.x.

    Article  PubMed  Google Scholar 

  29. Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26(6):519–32. doi:10.1007/s10875-006-9047-x.

    Article  PubMed  Google Scholar 

  30. Martinez-Martinez L, Vazquez-Ortiz M, Gonzalez-Santesteban C, Martin-Nalda A, Vicente A, Plaza AM, et al. From Severe Combined Immunodeficiency to Omenn syndrome after hematopoietic stem cell transplantation in a RAG1 deficient family. Pediatr Allergy Immunol. 2012;23(7):660–6. doi:10.1111/j.1399-3038.2012.01339.x.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Public Welfare Scientific Research Project of China (Grant No. 201402012) and the Natural Science Foundation of China (Grants No. 81202365 and 81172878). We are grateful to the children and their families who participated in the study. We sincerely appreciate the clinical assistance of Drs. Jie Yu, Yongchun Su, Ying Dou, and Jianwen Xiao. We are extremely grateful to the research assistant Wei Liu for providing guidance with techniques.

Author information

Author notes

    Authors and Affiliations

    1. Research Center for Immunologic and Infectious Diseases, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

      Xiaoming Bai, Jing Liu, Chaohong Liu, Yongjie Zhang, Wenjing Tang, Rongxin Dai, Liping Jiang & Xiaodong Zhao

    2. Division of Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

      Zhiyong Zhang, Junfeng Wu, Xuemei Tang, Yu Zhang, Yuan Ding & Xiaodong Zhao

    3. Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

      Xiaodong Zhao

    Authors
    1. Xiaoming Bai
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jing Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Zhiyong Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Chaohong Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yongjie Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Wenjing Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Rongxin Dai
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Junfeng Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xuemei Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Yu Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Yuan Ding
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Liping Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Xiaodong Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Xiaodong Zhao.

    Ethics declarations

    Conflicts of interest

    The authors have no potential financial conflicts of interest to declare.

    Ethical approval

    All procedures performed in studies involving human materials were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

    Additional information

    Xiaoming Bai and Jing Liu have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 1286 kb)

    Supplementary material 2 (DOCX 17 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Bai, X., Liu, J., Zhang, Z. et al. Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome. Immunol Res 64, 497–507 (2016). https://doi.org/10.1007/s12026-015-8723-4

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12026-015-8723-4

    Keywords

    Search

    Navigation