Impaired signaling downstream of IL-7 ( 12) and IL-21 ( 13– 17) explains, at least in part, the absence of T cells and impaired B-cell function, respectively, of X-SCID patients. These receptors’ engagement is crucial to lymphocyte activation, proliferation, and function. The extracellular domain of the chain is encoded by exons 1–5, followed by a transmembrane domain encoded by exon 6, while the two last exons encode the intracellular portion which can cooperate with the Janus kinase family member 3 (JAK3) ( 9, 10), a signaling kinase that interacts with other JAK and STAT proteins in complex signal transduction through common gamma chain of cytokine receptor subfamily ( 11). The γc protein is expressed on the surface of lymphoid, myeloid, and hematopoietic progenitor cells. X-SCID is caused by hemizygous pathogenic variants of the interleukin 2 receptor gamma ( IL2RG) gene, organized in eight exons that encode the common γ chain, (IL-2Rγ or γc, also known as CD132), which is a part of the IL-2 high-affinity receptor and several interleukin receptors, including those for IL-4, IL-7, IL-9, IL-15 and IL-21 ( 7, 8). The infections may be viral, bacterial, and/or fungal, and vaccination with BCG may lead to disseminated infection ( 6). Most infants with SCID die within their first year of life in the absence of immune reconstitution via hematopoietic stem cell transplantation, due to severe and recurrent infections that begin in the first months of life, frequently associated with diarrhea and growth retardation. X-linked severe combined immunodeficiency (X-SCID) is a life-threatening inborn error of immunity, accounts for approximately half of all cases of SCID ( 1– 5). Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies. Further analysis revealed a decreased percentage of CD4 + T cells capable of secreting IFN-γ, but not IL-4 or IL-17. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. Surface expression of IL-2Rγ was reduced on his lymphocytes. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. The patient suffered from recurrent sinopulmonary infections and refractory eczema. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A p. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
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