Alt. symbols: SCIDX1 | IMD4 | CIDX | CD132

Approved name: interleukin 2 receptor subunit gamma
Alt. names: severe combined immunodeficiency, combined immunodeficiency, X-linked, interleukin 2 receptor, gamma

Location: Xq13.1: 71107404 - 71112108 (-)
Gene type: protein_coding, 8 transcripts.

Scores: LoFtool: 0.119000 | pLI: 0.95776447 | LOEUF: 0.209

HGNC: 6010

NCBI: 3561, RefSeq: NG_009088.1

Ensembl: ENSG00000147168.14

LRG_150 | Status: public

OMIM: 308380

Expression | ProteinAtlas

IL2RG encodes the common gamma chain subunit of at least 6 unique cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. In particular, signaling through heterotrimeric IL-2 receptor affects the growth and differentiation of lymphocytes, glioma cells, and monocyte lineage cells.

X-linked germline mutations in IL2RG cause a spectrum of immunodeficiencies ranging from 'typical' T-B+NK- severe combined immunodeficiency (SCID) [OMIM: 300400] to 'atypical' forms that are attenuated or delayed-onset, often featuring variable combined immunodeficiency (CID) accompanied by immune dysregulation and/or autoimmunity [OMIM: 312863]. In places without newborn screening, 'typical' X-SCID presents in male infants as failure to thrive, diarrhea, dermatitis, oral/diaper candidiasis, and recurrent, severe and/or persistent infections, particularly by opportunistic organisms(GeneReviews). Disseminated infections and neurologic manifestations are rarer. Immunophenotyping is notable for low numbers of T and NK cell subsets compared to age-matched normal controls, virtual absence of naïve CD45RA+ cells, and absent T-cell responses to stimulation by mitogens and antigens. 'Atypical' X-SCID presentations may vary and include recurrent sinorespiratory infections with bronchiectasis; Omenn syndrome, an immune dysregulatory condition characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum IgE and/or increased eosinophils, CID with recurrent infections and skin manifestations such as warts and dermatitis starting within the first years of life; immune dysregulation and autoimmunity associated with arthritis, rashes, gastrointestinal malabsorption, and/or short stature; or EBV-related lymphoproliferative complications including lymphoma or severe verrucous lesions (GeneReviews). Of note, IL2RG mutations remain the most common cause of SCID but accounted for no more than 20% of all cases in one study of 11 newborn screen programs in the US from 2008-2013 (PMID: 25138334). In general, there is a correlation between the genotype and the clinical and immunophenotypic severity of disease, with 'typical' disease associated with functionally null mutations resulting in a T–B+NK– immunophenotype, and 'atypical' disease due to hypomorphic mutations resulting production of a small amount of gene product or residual protein activity (GeneReviews). One notable exception is the Arg222Cys mutation, associated with both 'typical' and 'atypical' X-SCID phenotypes - all reported individuals with this variant have had opportunistic infections within the first year of life, despite the presence of nearly normal numbers of T cells and NK cells (PMID: 25042067); newborn screening may give false negative results (PMID: 15687233, 30683812, 33712943). Of note, somatic reversion/mosaicism has been described (PMID: 18728247, 26407811, 31186537); regulatory region variants may result in an atypical X-SCID immunophenotype (PMID: 28770187); and at least 5 large deletions have been reported (PMID: 8605324, 7557965, 10794430, 21184155, 22105576). [Load More]