Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Yujuan Hou,Markus Mezger,Hans Peter Gratz,Daniel A Mader,Justin S Antony,Derya Güngör,Guillermo Ureña-Bailén,Paul G Gratz,Tina Renno,Rupert Handgretinger,Karin Schilbach-Stückle,Elke Malenke

doi:10.3390/genes13010035

Yujuan Hou, Markus Mezger + Show 10 more

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https://doi.org/10.3390/genes13010035

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Abstract

Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.

Highlights

X-linked severe combined immunodeficiency (X-SCID) is an inherited and life-threatening primary immunodeficiency disorder (PID) that is caused by mutations in the interleukin-2 receptor gamma chain gene (IL2RG) [1]
The common gamma chain plays an important role in the proliferation and differentiation of lymphocytes, mutations in the IL2RG gene inevitably cause a lack of T cells and natural killer- (NK) cells, and non-functional B lymphocytes [5]
In this study we report a novel missense IL2RG mutation (c.458T > C) in three brothers with an atypical X-SCID phenotype diagnosed with recurrent chronic infections, slightly decreased CD4+ T cells and NK cell lymphocytes and abnormal immunoglobulins

Summary

Introduction

X-linked severe combined immunodeficiency (X-SCID) is an inherited and life-threatening primary immunodeficiency disorder (PID) that is caused by mutations in the interleukin-2 receptor gamma chain gene (IL2RG) [1]. The gene is located on the X-chromosome q13.1 and it encodes for the common gamma chain (γC ) which is a subunit of various interleukin receptors, such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and constitutes the high-affinity complex with the α and β chains complementing the IL-2 receptor. The common gamma chain plays an important role in the proliferation and differentiation of lymphocytes, mutations in the IL2RG gene inevitably cause a lack of T cells and natural killer- (NK) cells, and non-functional B lymphocytes [5]. In typical X-SCID, the lack of IL-2RG function leads to diverse defects in humoral and cellular immunity. Unless the immune system is reconstituted through bone marrow transplantation or gene therapy approaches, children die within the first two years of life [8]

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