International Journal of Hematology

, Volume 109, Issue 5, pp 603–611 | Cite as

A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency

  • Motoi YamashitaEmail author
  • Ryosuke Wakatsuki
  • Tamaki Kato
  • Tsubasa Okano
  • Shingo Yamanishi
  • Nobuko Mayumi
  • Mayuri Tanaka
  • Yumi Ogura
  • Hirokazu Kanegane
  • Shigeaki Nonoyama
  • Kohsuke Imai
  • Tomohiro Morio
Original Article


X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients’ T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.


X-linked severe combined immunodeficiency IL2RG Synonymous mutation Leaky Atypical 



Common γ chain


Hematopoietic stem cell transplant


Human papilloma virus


Janus kinase


Immunoglobulin kappa recombination excision circles


Natural killer


Peripheral blood mononuclear cells


Phosphorylated STAT5


Recent thymic emigrant


Reverse transcription-PCR


T-cell receptor


T-cell receptor recombination excision circles


Untranslated regions


X-linked severe combined immunodeficiency



We thank the patients and their families for their participation in this study. We also thank Tzuwen Yeh, Akihiro Hoshino, Keisuke Tanaka for their technical assistance and their helpful suggestions.


This work was funded by the Japan Society for the Promotion of Science Grant number 2299310 and Japan Agency for Medical Research and Development Grant numbers JP18kk0205002, JP18ek0109179.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12185_2019_2619_MOESM1_ESM.docx (874 kb)
Supplementary material 1 (DOCX 873 KB)


  1. 1.
    Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312:729–38.CrossRefGoogle Scholar
  2. 2.
    Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73:147–57.CrossRefGoogle Scholar
  3. 3.
    Puck JM, Deschênes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, et al. The interleukin-2 receptor γ chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993;2:1099–104.CrossRefGoogle Scholar
  4. 4.
    Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009;9:480–90.CrossRefGoogle Scholar
  5. 5.
    Gray PEA, Logan GJ, Alexander IE, Poulton S, Roscioli T, Ziegler J. A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency. Int J Immunogenet. 2015;42:11–4.CrossRefGoogle Scholar
  6. 6.
    Ginn SL, Smyth C, Wong M, Bennetts B, Rowe PB, Alexander IE. A novel splice-site mutation in the common gamma chain (gammac) gene IL2RG results in X-linked severe combined immunodeficiency with an atypical NK + phenotype. Hum Mutat. 2004;23:522–3.CrossRefGoogle Scholar
  7. 7.
    Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, et al. Late-onset combined immunodeficiency with a novel IL2RG mutation and probable revertant somatic Mosaicism. J Clin Immunol. 2015;35:610–4.CrossRefGoogle Scholar
  8. 8.
    Hsu AP, Pittaluga S, Martinez B, Rump AP, Raffeld M, Uzel G, et al. IL2RG reversion event in a common lymphoid progenitor leads to delayed diagnosis and milder phenotype. J Clin Immunol. 2015;35:449–53.CrossRefGoogle Scholar
  9. 9.
    Kuijpers TW, van Leeuwen EMM, Barendregt BH, Klarenbeek P, aan de Kerk DJ, Baars PA, et al. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8 + T cells. Haematologica. 2013;98:1030–8.CrossRefGoogle Scholar
  10. 10.
    Kawai T, Saito M, Nishikomori R, Yasumi T, Izawa K, Murakami T, et al. Multiple reversions of an IL2RG mutation restore T cell function in an X-linked severe combined immunodeficiency patient. J Clin Immunol. 2012;32:690–7.CrossRefGoogle Scholar
  11. 11.
    Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, et al. Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency. Blood. 2008;112:4090–7.CrossRefGoogle Scholar
  12. 12.
    Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles. J Allergy Clin Immunol. 2013;131:1437–40.e5.CrossRefGoogle Scholar
  13. 13.
    Okano T, Tsujita Y, Kanegane H, Mitsui-Sekinaka K, Tanita K, Miyamoto S, et al. Droplet digital PCR-based chimerism analysis for primary immunodeficiency diseases. J Clin Immunol. 2018;38:300–6.CrossRefGoogle Scholar
  14. 14.
    Fuchs S, Rensing-Ehl A, Erlacher M, Vraetz T, Hartjes L, Janda A, et al. Patients with T+/low NK+ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency. Eur J Immunol. 2014;44:3129–40.CrossRefGoogle Scholar
  15. 15.
    Mella P, Imberti L, Brugnoni D, Pirovano S, Candotti F, Mazzolari E, et al. Development of autologous T lymphocytes in two males with X-linked severe combined immune deficiency: molecular and cellular characterization. Clin Immunol. 2000;95:39–50.CrossRefGoogle Scholar
  16. 16.
    Sharfe N, Shahar M, Roifman CM. An interleukin-2 receptor gamma chain mutation with normal thymus morphology. J Clin Invest. 1997;100:3036–43.CrossRefGoogle Scholar
  17. 17.
    Stepensky P, Keller B, Shamriz O, Spee-Mayer von C, Friedmann D, Shadur B, et al. T + NK + IL-2 Receptor γ Chain Mutation: a Challenging Diagnosis of Atypical Severe Combined Immunodeficiency. J Clin Immunol. 2018;38:527–36.CrossRefGoogle Scholar
  18. 18.
    Niemela JE, Puck JM, Fischer RE, Fleisher TA, Hsu AP. Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency. Clin Immunol. 2000;95:33–8.CrossRefGoogle Scholar
  19. 19.
    Puck JM, Pepper AE, Henthorn PS, Candotti F, Isakov J, Whitwam T, et al. Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. Blood. 1997;89:1968–77.Google Scholar
  20. 20.
    Sahashi K, Masuda A, Matsuura T, Shinmi J, Zhang Z, Takeshima Y, et al. In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5′ splice sites. Nucleic Acids Res. 2007;35:5995–6003.CrossRefGoogle Scholar
  21. 21.
    Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67.CrossRefGoogle Scholar
  22. 22.
    Mazzolari E, Forino C, Guerci S, Imberti L, Lanfranchi A, Porta F, et al. Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency. J Allergy Clin Immunol. 2007;120:892–9.CrossRefGoogle Scholar
  23. 23.
    Marini A, Niehues T, Stege H, Ruzicka T, Hengge UR. Plantar warts in twins after successful bone marrow transplantation for severe combined immunodeficiency. J Dtsch Dermatol Ges. 2006;4:417–20.CrossRefGoogle Scholar
  24. 24.
    Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, et al. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012;122:3769–80.CrossRefGoogle Scholar
  25. 25.
    Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002;4:1545–58.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Motoi Yamashita
    • 1
    Email author
  • Ryosuke Wakatsuki
    • 2
  • Tamaki Kato
    • 3
    • 4
  • Tsubasa Okano
    • 1
  • Shingo Yamanishi
    • 5
  • Nobuko Mayumi
    • 6
  • Mayuri Tanaka
    • 6
  • Yumi Ogura
    • 3
  • Hirokazu Kanegane
    • 1
    • 7
  • Shigeaki Nonoyama
    • 3
  • Kohsuke Imai
    • 1
    • 8
  • Tomohiro Morio
    • 1
  1. 1.Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental SciencesTokyo Medical and Dental University (TMDU)TokyoJapan
  2. 2.School of Medicine, Faculty of MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
  3. 3.Department of PediatricsNational Defense Medical CollegeSaitamaJapan
  4. 4.Department of PediatricsSelf-Defense Forces Central HospitalTokyoJapan
  5. 5.Department of PediatricsNippon Medical SchoolTokyoJapan
  6. 6.Department of DermatologyNippon Medical SchoolTokyoJapan
  7. 7.Department of Child Health and DevelopmentTokyo Medical and Dental University (TMDU)TokyoJapan
  8. 8.Department of Community Pediatrics, Perinatal and Maternal MedicineTokyo Medical and Dental University (TMDU)TokyoJapan

Personalised recommendations