So far, according to the VarSome database, 284 known variants in the IL2RG gene are observed, of which 147 are pathogenic, 51 are uncertain, and 86 are benign ( 8). Together with the IL-2Ra and IL-2Rb subunits, γc composes the cellular receptor for IL-2 and is essential for its signal transduction through activation of JAK3 tyrosine kinase ( 6, 7). It consists of three domains: extracellular (carries the gene for family conserved cysteines and repeated tryptophan and serine motifs), transmembrane, and intracellular. The γc molecule is expressed on the cell surface of lymphoid, myeloid cells, and hematopoietic progenitors ( 4, 5). The IL2RG gene spans 4.5 kb of genomic DNA organized in 8 exons and encodes a protein of 369 amino acids. SCIDX-1 is caused by mutations of IL2RG, the gene encoding a common gamma chain (also known as γc or CD132), which is a transmembrane protein shared by cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 ( 2, 3). Among them, inherited in an X-linked manner SCID (SCIDX-1, X-SCID) is the most prevalent, accounting for approximately half of the cases of SCID, with an estimated incidence of 1:130,000 live births ( 1). Severe combined immunodeficiency (SCID) is a group of inherited disorders responsible for life-threatening dysfunctions of the immune system. In order to evaluate the effect of this unreported variant on the protein structure, a structural modeling process was performed showing prominent biochemical alterations of the protein features, including molecular weight, isoelectric charge, and possible changes to its secondary and tertiary structure. He manifested recurrent infections of the gastrointestinal tract, whereas his twin brother was asymptomatic with no immune defects. The patient was born from a twin pregnancy. In this study, we report a 4-month-old boy with T −B +NK − severe combined immunodeficiency (SCID) due to a novel mutation in exon 2 of IL2RG, the gene encoding the interleukin (IL) common gamma chain (γc) of the cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. 3Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.2Department of Clinical Immunology, University Children Hospital, Krakow, Poland.1Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Kraków, Poland.There are no restrictions on its use.Magdalena Rutkowska-Zapała 1 † Anna Szaflarska 1 † Anna Kluczewska 1 Julia Ciȩciwa 2 Jacek Plewka 3 Anna Michalska 2 Maciej Siedlar 1 * Specific mutation diagnosis thus remains technically challenging, but it is important for genetic counseling and perhaps for helping to select appropriate subjects for retroviral gene therapy trials, This is a US government work. Abnormal gamma c chains may be expressed in the lymphocytes of as many as two thirds of patients with X-linked SCID. Although skewed maternal X chromosome inactivation, single-strand conformation polymorphism, mRNA expression, and cell surface staining with anti-gamma c antibodies were all helpful in establishing IL2RG defects as the cause of SCID, only dideoxy fingerprinting and DNA sequence determination each detected 100% of the IL2RG mutations in our series. Sixty-two different mutations spanning all eight IL2RG exons were found in 87 cases, making possible correlations between mutation type and functional consequences. To investigate the frequency and variety of IL2RG mutations that cause SCID, we analyzed DNA, RNA, and B-cell lines from a total of 103 unrelated SCID-affected males and their relatives using a combination of molecular and immunologic techniques. In humans, SCID is most commonly caused by mutations in the X-linked gene IL2RG, which encodes the common gamma chain, gamma c, of the leukocyte receptors for interleukin-2 and multiple other cytokines. Severe combined immunodeficiency (SCID) is a syndrome of profoundly impaired cellular and humoral immunity.
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