8/21/2023 0 Comments Leaky scid![]() ![]() In the 1990s, descriptions emerged of patients with IL2RG mutations and a milder phenotype, showing atypical manifestations and prolonged survival. The disease is lethal within the first 2 years of life unless patients undergo prompt hematopoietic stem cell transplantation (HSCT) or gene therapy 7, 11, 12. Patients with X‐SCID are prone to severe recurrent and persistent infections caused by certain bacteria, viruses and fungi in their first 6 months of life and may experience chronic diarrhea, skin rashes and failure to thrive 10. The absence of T cells also leads to non‐functional B cells and hypogammaglobulinemia, despite a normal B cell count (T –B +NK – immunophenotype) 7, 8, 9. Once STAT‐5 is phosphorylated, it dimerizes and translocates into the nucleus, transcribing genes involved in proliferation, survival, differentiation and apoptosis of T and natural killer (NK) cells 6.īecause of impaired cytokine signaling, children with complete γ c deficiency lack T and NK cells. ![]() IL‐2Rβ and IL‐2Rγ selectively recruit JAKl and JAK3, respectively, bringing them into close proximity, and they cross‐phosphorylate each other, activating STAT‐5. When IL‐2 binds to IL‐2Rα, all the subunits trimerize. The IL‐2 receptor consists of three subunits: IL‐2Rα, IL‐2Rβ and IL‐2Rγ. γ c is a transmembrane protein shared by various cytokine receptors – interleukin (IL)‐2, IL‐4, IL‐7, IL‐9, IL‐15 and IL‐21 – that transduces signals through a Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway 4, 5. X‐linked severe combined immunodeficiency (X‐SCID) (OMIM 208380) is an inherited disorder of the immune system caused by inborn errors in the interleukin‐2 receptor subunit gamma ( IL2RG) gene, which encodes a common gamma chain, referred to as γ c or CD132 1, 2, 3. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes. We identified a region of three amino acids in the γ c intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Here, we describe how the R328X mutation in IL‐2RG may allow partial phosphorylation of STAT‐5 through a JAK3‐independent pathway. Co‐immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γ c. After confirming normal IL‐2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription‐1 (STAT‐5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γ c), which showed partially preserved function. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4‐year‐old boy with lethal Epstein–Barr virus‐related lymphoma and his asymptomatic 8‐month‐old brother with a T lowB +natural killer (NK) + immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. In addition to their detection in typical X‐linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)‐2 receptor common gamma chain gene ( IL2RG) have been described in patients with atypical clinical and immunological phenotypes.
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