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

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Abstract

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.

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Abbreviations

γc:

Common γ chain

HSCT:

Hematopoietic stem cell transplant

HPV:

Human papilloma virus

JAK:

Janus kinase

KRECs:

Immunoglobulin kappa recombination excision circles

NK:

Natural killer

PBMCs:

Peripheral blood mononuclear cells

pSTAT5:

Phosphorylated STAT5

RTE:

Recent thymic emigrant

RT-PCR:

Reverse transcription-PCR

TCR:

T-cell receptor

TRECs:

T-cell receptor recombination excision circles

UTRs:

Untranslated regions

X-SCI:

X-linked severe combined immunodeficiency

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Motoi Yamashita, Tsubasa Okano, Hirokazu Kanegane, Kohsuke Imai & Tomohiro Morio

  2. School of Medicine, Faculty of Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Ryosuke Wakatsuki

  3. Department of Pediatrics, National Defense Medical College, Saitama, Japan

    Tamaki Kato, Yumi Ogura & Shigeaki Nonoyama

  4. Department of Pediatrics, Self-Defense Forces Central Hospital, Tokyo, Japan

    Tamaki Kato

  5. Department of Pediatrics, Nippon Medical School, Tokyo, Japan

    Shingo Yamanishi

  6. Department of Dermatology, Nippon Medical School, Tokyo, Japan

    Nobuko Mayumi & Mayuri Tanaka

  7. Department of Child Health and Development, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Hirokazu Kanegane

  8. Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Kohsuke Imai

Authors
  1. Motoi Yamashita
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  2. Ryosuke Wakatsuki
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  3. Tamaki Kato
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  4. Tsubasa Okano
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  5. Shingo Yamanishi
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  6. Nobuko Mayumi
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  7. Mayuri Tanaka
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  8. Yumi Ogura
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  9. Hirokazu Kanegane
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  10. Shigeaki Nonoyama
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  11. Kohsuke Imai
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  12. Tomohiro Morio
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Correspondence to Motoi Yamashita.

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Yamashita, M., Wakatsuki, R., Kato, T. et al. A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency. Int J Hematol 109, 603–611 (2019). https://doi.org/10.1007/s12185-019-02619-9

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  • DOI: https://doi.org/10.1007/s12185-019-02619-9

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