IL21R was first reported in relation to autosomal recessive Immunodeficiency 56 in 2013 (PMID: 23440042). The protein encoded by this gene is a cytokine receptor for interleukin 21 (IL21). IL21R has been shown to form a heterodimeric receptor complex with the common gamma-chain, a receptor subunit also shared by the receptors for interleukin 2, 4, 7, 9, and 15. This receptor transduces the growth promoting signal of IL21 with pleiotropic effects on many immune cell types, including promoting CD8+ T cell activation and proliferation, NK cell maturation and cytotoxicity, differentiation of CD4+ T cells, including regulatory T cells, in addition to B cells proliferation, memory B cell formation, isotype switching, and differentiation to plasma cells (PMID: 33929673).
This gene-disease relationship is supported by both genetic and experimental evidence. At least eight variants (missense, splice site, deletion, nonsense and frameshift) have been reported in thirteen probands (PMIDs: 23440042, 25769540, 17234735, and 33929673). The main clinical manifestations were recurrent bacterial, fungal, and viral infections; cryptosporidiosis-associated cholangitis; and asthma (PMID: 33929673). The reported biallelic IL21R variants has been shown to result in functional defects in T cells and impaired generation of memory B cells and induction of class switching (PMID: 33929673). A major role of IL21R in immune system regulation has been demonstrated by the sustained Treg defect detected in Il2−/−Il21r−/− double knockout mice (PMID: 24446516).
In summary, IL21R is definitively associated with autosomal recessive immunodeficiency, 56. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.
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