A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency
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.
KeywordsX-linked severe combined immunodeficiency IL2RG Synonymous mutation Leaky Atypical
Common γ chain
Hematopoietic stem cell transplant
Human papilloma virus
Immunoglobulin kappa recombination excision circles
Peripheral blood mononuclear cells
Recent thymic emigrant
T-cell receptor recombination excision circles
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.
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