Disease relevance of IL2RG

• The IL2RG gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human Xq13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID) [1].
• Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities [2].
• CONCLUSIONS: These results suggest that non-small cell lung cancer cells may express functional cytokine receptors, including the interleukin 2 receptor gamma-chain commonly found in association with the lymphocyte interleukin 2 receptor [3].
• We compared transduction of autologous B-cell lines and granulocyte colony-stimulating factor-mobilized peripheral CD34(+) cells from these patients using an MFGS retrovirus vector containing the gamma(c) gene IL2RG pseudotyped with amphotropic, gibbon ape leukemia virus, or RD114 envelopes [4].
• Using a mouse model for gene therapy of X-SCID, we find that the corrective therapeutic gene IL2RG itself can act as a contributor to the genesis of T-cell lymphomas, with one-third of animals being affected [5].

High impact information on IL2RG

• The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID [6].
• Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans [7].
• Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor [8].
• Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor [9].
• Analysis of thymus RNA indicated that many of these rearrangements are expressed as V gamma-(D delta)-J delta-C delta and V delta-(D delta)-J gamma-C gamma transcripts [10].

Chemical compound and disease context of IL2RG

• Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor gamma-chain-knocked-out AIDS mouse model [11].
• The p64 inducibility was dramatically reduced in resistant HOB1 cells or unrelated cell lines which show phenotypic resistance to adriamycin toxicity [12].
• Quantitative analysis of islet glutamic acid decarboxylase p64 autoantibodies in insulin-dependent diabetes mellitus [13].

Biological context of IL2RG

• Mutation detection in the pedigree confirmed that the founder grandmother's somatic cells had only normal IL2RG, and further showed that the SCID-associated X chromosome haplotype was inherited by three daughters, one with a wild type IL2RG gene and two others with the insertional mutation [1].
• Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226 [14].
• Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor gamma chain (IL2RG) [14].
• For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing [14].
• Unique point mutations were documented to be specifically associated with the disease and the carrier state in four unrelated affected males and their family members: one in a boy with no detectable IL2RG mRNA, in which the mutation ablated a splice donor site; one causing premature chain termination; and two causing distinct amino acid changes [15].

Anatomical context of IL2RG

• Using fluorescence in situ hybridization and PCR amplification of somatic cell hybrid DNAs, we mapped IL2RG to human Xq13.1, a location within the SCIDX1 critical region established by linkage analysis [15].
• Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells [16].
• Fibroblasts also constitutively transcribed the genes coding for IL-2R alpha and IL-2R beta and accumulated their respective mRNAs but failed to exhibit the IL-2R gamma-chain on the mRNA and protein level [17].
• The ability of these mutated IL-2R gamma chains to participate in the function of a high-affinity IL-2R complex was examined by radiolabeled IL-2 binding studies using Epstein-Barr virus-transformed B lymphoblastoid cell lines (B-LCL) derived from SCIDX1 patients [18].
• These SCIDX1 mutations confirm the critical role of the IL-2R gamma chain in T cell and NK cell development [18].

Associations of IL2RG with chemical compounds

• IL-2-induced signal transduction: involvement of tyrosine kinase and IL-2 receptor gamma chain [19].
• A C-to-T transition was demonstrated in exon 5 of the IL2RG gene, resulting in the substitution of tryptophan for arginine at position 224 [20].
• The point mutation that we have detected is C to T, which results in one amino acid substitution of valine for alanine in the extracellular domain of the IL-2R gamma-chain (named AV mutant) [21].
• Parallel analysis of the two T cell substrates (64,000 and 58,000 daltons, p64 and p58) showed that they also contained two phosphotyrosine sites that were identical [22].
• In the present study, fluorescein-activated cell sorter analysis revealed that the ability of IL-15 to enhance neutrophil phagocytosis is not a result of increased expression of IL-15Ralpha, CD122, or CD132 on the neutrophil cell surface [23].

Physical interactions of IL2RG

• IL-4 receptor complexes containing or lacking the gamma C chain are inhibited by an overlapping set of antagonistic IL-4 mutant proteins [24].
• Kinetic analysis of high affinity forms of interleukin (IL)-13 receptors: suppression of IL-13 binding by IL-2 receptor gamma chain [25].
• These results suggest that fibrinogen has potentially significant novel alpha v beta 3 binding sites in gamma C and alpha EC [26].

Regulatory relationships of IL2RG

• Involvement of the IL-2 receptor gamma-chain (gammac) in the control by IL-4 of human monocyte and macrophage proinflammatory mediator production [27].
• In fact, co-treatment of monocytes with IL-2 and IL-4 increased the expression of IL-2R gamma chain above the levels induced by IL-2 alone, whereas it did not significantly affect the expression of IL-2R beta chain [28].
• Here we used mammalian cells expressing recombinant alpha v beta 3 to show that recombinant alpha EC and gamma C domains expressed in bacteria specifically bind to alpha v beta 3 [26].

Other interactions of IL2RG

• In contrast, IL-2 decreased transcription from the IL-2 receptor gamma chain promoter [29].
• X-linked severe combined immunodeficiency (SCIDX1) is an inherited disease characterized by profound abnormalities of cell-mediated and humoral immunity [30].
• The interleukin-2 receptor gamma chain (IL2Rgamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2 [31].
• Expression of the p75 IL-2Rbeta- and the p64 IL-2Rgamma-chain was a common finding in most of the myeloid cell samples investigated, whereas IL-2Ralpha-chain was less frequently expressed [32].
• This effect was found to involve down-regulation of the expression of both CD25 (IL-2R alpha) and CD122 (IL-2R beta) on the lymphocyte membrane and a marked decrease in the level of up-regulation of the expression of surface CD132 (IL-2R gamma or gamma(c)) [33].

Analytical, diagnostic and therapeutic context of IL2RG

• The specific pathogenesis of IL2RG mutations and approaches to gene therapy can now be addressed in the X-linked form of SCID [15].
• In this study the IL2RG gene of 31 patients with severe combined immunodeficiency (SCID) was examined by nonradioactive single-strand conformation polymorphism and sequence analysis [34].
• Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R gamma-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown [35].
• 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 [36].
• For many women at risk for carrying an IL2RG mutation, no samples were saved from an affected male relative prior to either death or bone marrow transplantation (BMT) [37].

References