IL2RG Gene Research Articles

Mutation analysis by a non-radioactive single-strand conformation polymorphism assay in nine families with X-linked severe combined immunodeficiency (SCIDX1).

X-linked severe combined immunodeficiency (SCIDX1) is an inherited disease characterized by profound abnormalities of cell-mediated and humoral immunity. Patients with SCIDX1 have defects in the common cytokine receptor gamma chain gene (IL2RG) that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9 and IL-15. We have characterized nine SCIDX1 families by using a DNA-based, non-radioactive screening method and DNA sequencing. Nine different mutations were found, scattered from exon 1 to exon 5 of the IL2RG gene. Two of these mutations have been previously identified in other unrelated patients; the other seven are novel mutations that differ from all of the 95 already reported in the IL2RG mutation data base. In addition to describing novel mutations in the IL2RG gene, this study shows that the knowledge of the genetic defect and the use of an efficient, non-radioactive, and rapid screening approach have important implications for prenatal and postnatal diagnosis, carrier female identification, and possibly prenatal therapy.

Further Analysis of Interleukin-2 Receptor Subunit Expression on the Different Human Peripheral Blood Mononuclear Cell Subsets

We have investigated the expression of the three components of the interleukin-2 receptor (IL-2Rα, IL-2Rβ, and IL-2Rγ) on the surface of the various peripheral blood mononuclear cell (PBMC) subsets by flow cytometry analysis. The PBMC were immediately isolated (ficoll) from blood collected on heparin as anticoagulant. The three IL-2R components are absent or only marginally detectable on CD4 T lymphocytes. No expression of the IL-2R chains is found for the B lymphocytes. In most donors, the three chains are not detectable on CD8 T lymphocytes, but for a few of them, IL-2Rβ or IL-2Rγ are clearly expressed. CD56 high (IL-2Rα+) and CD56 low (IL-2Rα−) natural killer (NK) cells express IL-2Rβ, but not IL-2Rγ. IL-2Rγ is expressed by monocytes of all donors although with variable intensity. When blood is collected on other anticoagulants or when cells are isolated 1 day after collection, IL-2Rα, IL-2Rβ, and IL-2Rγ are largely expressed on the surface of most PBMC. This observation provides a possible explanation for divergent data previously reported on IL-2R expression. Finally, we show that IL-2Rγ, which is not detectable on the cell surface of lymphocytes, is nevertheless expressed and stored as an intracellular component. This result is in agreement with the constitutive expression of the IL-2Rγ gene and suggests a specific regulatory mechanism for IL-2Rγ membrane translocation.

Further Analysis of Interleukin-2 Receptor Subunit Expression on the Different Human Peripheral Blood Mononuclear Cell Subsets

AbstractWe have investigated the expression of the three components of the interleukin-2 receptor (IL-2Rα, IL-2Rβ, and IL-2Rγ) on the surface of the various peripheral blood mononuclear cell (PBMC) subsets by flow cytometry analysis. The PBMC were immediately isolated (ficoll) from blood collected on heparin as anticoagulant. The three IL-2R components are absent or only marginally detectable on CD4 T lymphocytes. No expression of the IL-2R chains is found for the B lymphocytes. In most donors, the three chains are not detectable on CD8 T lymphocytes, but for a few of them, IL-2Rβ or IL-2Rγ are clearly expressed. CD56 high (IL-2Rα+) and CD56 low (IL-2Rα−) natural killer (NK) cells express IL-2Rβ, but not IL-2Rγ. IL-2Rγ is expressed by monocytes of all donors although with variable intensity. When blood is collected on other anticoagulants or when cells are isolated 1 day after collection, IL-2Rα, IL-2Rβ, and IL-2Rγ are largely expressed on the surface of most PBMC. This observation provides a possible explanation for divergent data previously reported on IL-2R expression. Finally, we show that IL-2Rγ, which is not detectable on the cell surface of lymphocytes, is nevertheless expressed and stored as an intracellular component. This result is in agreement with the constitutive expression of the IL-2Rγ gene and suggests a specific regulatory mechanism for IL-2Rγ membrane translocation.

Molecular cloning of the cDNA coding sequence of IL-2 receptor-γ (γ c) from human and murine forebrain: Expression in the hippocampus in situ and by brain cells in vitro

IL-2 has been implicated in various neurobiological processes of the mammalian CNS. To understand how IL-2 acts in the brain, our lab has sought to determine the molecular pharmacological characteristics of brain IL-2 receptors (IL-2R). The lymphocyte IL-2Rγ, an essential subunit for IL-2 signaling, is also a common subunit (γ c) for multiple immune cytokine receptors (e.g., IL-4R, IL-7R, IL-9R, IL-15R). Having previously cloned the α and β subunits of the IL-2R heterotrimer complex from normal murine forebrain, we examined the hypothesis that the brain IL-2Rγ is derived from the same or a closely related gene coding sequence as that expressed by lymphocytes. In this study, we cloned and sequenced the full-length IL-2Rγ coding region from saline-perfused mouse forebrain and from a human hippocampal library. The cDNA sequences of IL-2Rγ from human and murine brain were 100% homologous to their lymphocyte sequences. Northern blot analysis showed that the mRNA transcripts in murine brain were the expected size, but the predominant transcript expressed in the brain was different than in the spleen. Compared to the spleen, very low levels of IL-2Rγ were expressed in the forebrain. In the murine hippocampus, a region where a number of neurobiological actions of IL-2 have been reported, IL-2Rγ mRNA was detected over the dentate gyrus and CA1–CA4 by in situ hybridization histochemistry. IL-2Rγ was found to be constitutively expressed by murine HN33.dw hippocampal neuronal cells, murine NB41A3 neuroblastoma cells, astrocyte-enriched mixed glial cell cultures, and in SCID mouse forebrain. The human cortical neuronal cell lines, HCN-1A and HCN-2, did not express the IL-2Rγ gene. These data suggest the possibility that, in addition to being essential in IL-2 signaling in brain, IL-2Rγ could be a common subunit (γ c) for multiple cytokine receptors which may be operative in the mammalian CNS.

In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1)

X-linked severe combined immunodeficiency (SCIDXI) is an inherited immune defect which leads to death in infancy from severe infections. The defect is caused by mutations of the IL-2RG gene that encodes for the common gamma chain shared by several cytokine receptors. The disease is characterised by lack of T and NK cells with normal numbers of B cells. SCIDXI can be cured by bone marrow transplantation (BMT) or prevented by abortion after prenatal diagnosis. A male fetus was diagnosed as having SCIDXI by molecular, immunophenotypic, and functional analyses. The fetus was injected intraperitoneally under ultrasound guidance with CD34 haematopoietic progenitor cells purified from paternal bone marrow and T-cell depleted by E rosetting. Chimerism analysis was by HLA-DQ alpha typing and gamma-chain staining on cord blood. A healthy 3.6 kg boy was delivered by caesarean section at 38 weeks of gestation with no clinical or laboratory signs of graft-versus-host disease. Engraftment of donor-derived CD2 cells was found at birth. At 3.5 months of age the infant is well and his T-cell counts and function are normal. In-utero transplantation of haematopoietic progenitor cells allowed immune reconstitution of a fetus with SCIDXI and may be an alternative to elective abortion. Our report should encourage applications of this method to other inherited disorders curable by BMT.

Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency.

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). In a large Canadian pedigree genetic linkage studies demonstrated that the proband's grandmother was the source of an X-linked SCID mutation. However, her T cells did not show the expected skewed X chromosome inactivation pattern of female carriers of SCID, despite her having one affected son and two carrier daughters with skewed X inactivation. Single strand conformation polymorphism analysis of IL2RG in the affected proband was abnormal in exon 5; sequencing revealed a nine nucleotide in-frame duplication insertion. The three duplicated amino acids included the first tryptophan of the "WSXWS" motif found in all members of the cytokine receptor gene superfamily. 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. Female germ line mosaicism is unusual, but its presence in this X-linked SCID family emphasizes the limitations of genetic diagnosis by linkage as compared with direct mutation analysis.

Intronic point mutation in the IL2RG gene causing X-linked severe combined immunodeficiency.

Journal Article Intronic point mutation in the IL2RG gene causing X-linked severe combined immunodeficiency Get access Carla Tassara, Carla Tassara Laboratory for Gene Transfer, National Center for Human Genome Research, National Institutes of Health, Building 49, Room 3W14, 49 Convent Drive, Bethesda, MD 20892–4470USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Amy E. Pepper, Amy E. Pepper Laboratory for Gene Transfer, National Center for Human Genome Research, National Institutes of Health, Building 49, Room 3W14, 49 Convent Drive, Bethesda, MD 20892–4470USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Jennifer M. Puck Jennifer M. Puck * Laboratory for Gene Transfer, National Center for Human Genome Research, National Institutes of Health, Building 49, Room 3W14, 49 Convent Drive, Bethesda, MD 20892–4470USA *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 4, Issue 9, September 1995, Pages 1693–1695, https://doi.org/10.1093/hmg/4.9.1693 Published: 01 September 1995 Article history Received: 01 June 1995 Revision received: 12 June 1995 Accepted: 12 June 1995 Published: 01 September 1995

IL-2Rγ Gene Microdeletion Demonstrates That Canine X-Linked Severe Combined Immunodeficiency Is a Homologue of the Human Disease

X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the gamma chain of the IL-2 receptor (IL-2R gamma). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R gamma gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID.

INTERLEUKIN-2 RECEPTOR γ CHAIN MUTATION RESULTS IN X-LINKED SEVERE COMBINED IMMUNODEFICIENCY IN HUMANS

Purpose of the Study. Interleukin-2 (IL-2) and IL-2 receptors play a critical role in the regulation of the T cell immune response. IL-2 receptors are made of combinations of three different chains a, β, and γ. Different combinations of these chains result in the formation of three different classes of IL-2 receptors. The authors of this paper were interested in the interleukin-2 receptor γ chain (IL-2Rγ) gene and its relationship to X-linked severe combined immunodeficiency (XSCID). Findings. The IL-2Rγ gene was localized to the X chromosome in the same region as the XSCID locus. The IL-2Rγ gene from three patients with XSCID were found to have point mutations leading to premature stop codons and truncated IL-2Rγ chains. These shortened IL-2Rγ chains lack the cytoplasmic domain required for cell signal transduction. Reviewers' Comments. This is the first article showing the XSCID is associated with mutations in the IL-2Rγ gene. This suggests that IL-2Rγ plays a critical role in the early development of T-cells and their function in the immune system. These results also suggest that other genetic defects in components of the IL-2/IL-2R system could be responsible for other forms of SCID or other immunodeficiency syndromes. The fact that all three patients had different mutations suggests that there is no single dominant mutation. These findings have important implications for prenatal and postnatal diagnosis, carrier identification, and possibly gene therapy for XSCID.

Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans

The interieukin-2 (IL-2) receptor γ chain (IL-2Rγ) is a component of high and intermediate affinity IL-2 receptors that is required to achieve full ligand binding affinity and internalization. We have localized the IL-2Rγ gene to human chromosome Xq13. Genetic linkage analysis indicates that the IL-2Rγ gene and the locus for X-linked severe combined immunodeficiency (XSCID) appear to be at the same position. Moreover, we demonstrate that each of three unrelated patients with XSCID has a different mutation in his IL-2Rγ gene resulting in a different premature stop codon and predicted C-terminal truncation. These data establish that XSCID is associated with mutations of the IL-2Rγ gene product. Since XSCID is characterized by absent or markedly reduced numbers of T cells, our findings imply that IL-2Rγ plays a vital role in thymic maturation of T cells. These results also have important implications for prenatal and postnatal diagnosis, carrier female detection, and gene therapy for XSCID.

The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1.

The gene encoding the gamma chain of the lymphocyte interleukin-2 receptor has been cloned and shown to be required to associate with the beta chain in order for IL-2 internalization and cell activation to occur (1). We considered this gene, IL2RG, a candidate for the X-linked form of severe combined immunodeficiency at the SCIDX1 locus, in which affected males have impaired lymphocyte development. 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. The 4.2 kb IL2RG gene was sequenced, and its genomic organization was elucidated. Seven of 19 transformed B-lymphocyte cell lines with independent SCIDX1 mutations had absent or minimal IL2RG mRNA. 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. The demonstration of impaired IL2RG mRNA expression in males with X-linked SCID and of unique point mutations in SCIDX1 pedigrees constitutes powerful evidence that the SCIDX1 gene is IL2RG. Noguchi et al. (2) have independently published IL2RG mapping to Xq13 and discovery of mutations in three affected males. The specific pathogenesis of IL2RG mutations and approaches to gene therapy can now be addressed in the X-linked form of SCID.