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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

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.

Keywords

X-linked severe combined immunodeficiency IL2RG Synonymous mutation Leaky Atypical 

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

Notes

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.

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)

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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

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