International Journal of Hematology

DOI: 10.1007/s12185-019-02619-9 Pages: 603-611

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

1. Tokyo Medical and Dental University (TMDU), Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences

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

3. National Defense Medical College, Department of Pediatrics

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

5. Nippon Medical School, Department of Pediatrics

6. Nippon Medical School, Department of Dermatology

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

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

Correspondence to:
Motoi Yamashita
Tel: +81-3-5803-5249
Email: myamashita.ped@tmd.ac.jp

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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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