Noguchi M, Yi H, Rosenblatt HM et al Interleukin‐2 receptor gamma chain mutation results in X‐linked severe combined immunodeficiency in humans. Takeshita T, Asao H, Ohtani K et al Cloning of the gamma chain of the human IL‐2 receptor. IL-2RG JAK1 JAK3 STAT-5 X-linked severe combined immunodeficiency hypomorphic mutations interleukin receptor common gamma subunit leaky SCID whole exome sequencing. 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 low B + 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. 8 Genetics Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain.7 Immunology Division, Department of Cell Biology, Physiology and Immunology, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.6 Hematopoietic Stem Cell Transplantation Unit, Pediatric Hematology and Oncology Department, Vall d'Hebron Campus Hospitalari, Barcelona, Spain.
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