Alt. symbols: GP130 | CD130 | sGP130

Approved name: interleukin 6 cytokine family signal transducer
Alt. names: interleukin 6 signal transducer (gp130, oncostatin M receptor) | gp130, oncostatin M receptor, Interleukin-6 receptor subunit beta

Location: 5q11.2: 55935095 - 55995022 (-)
Gene type: protein_coding, 25 transcripts.

Scores: LoFtool: 0.442000 | pLI: 0.99784278 | LOEUF: 0.228

HGNC: 6021

NCBI: 3572, RefSeq: .0

Ensembl: ENSG00000134352.21

LRG_ | Status: none

OMIM: 600694

Expression | ProteinAtlas

This gene encodes the glycoprotein 130 (GP130), a transmembrane protein forms part of many cytokine receptor complexes. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can all utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex that activates intracellular JAK-MAPK and JAK-STAT3 signaling pathways via phosphorylation of IL6ST tyrosine residues (PMID: 19915009, 2261637, 23294003). In mouse and human cells, GP130 also triggers STAT3-independent activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration (PMID: 25731159). GP130 also associates with the related tyrosine kinases SRC and YES, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. Knockout mouse models have also found an important role for GP130 in the control of bone homeostasis, with distinct effects from downstream signaling via the STAT and MAPK pathways (PMID: 14755335).

Both monoallelic and biallelic mutations in IL6ST have been associated with autosomal dominant (AD) and autosomal recessive (AR) forms of hyper-IgE syndrome (HIES) [OMIM: 618523]. Schwerd et al. (2017) reported the first simplex case with the identification of a homozygous missense (p.N404Y) mutation in a daughter of consanguineous south Asian parents who presented with recurrent infections, eczema, bronchiectasis, and skeletal abnormalities including craniosynostosis and progressive scoliosis, as well as immunophenotyping notable for elevated IgE levels (maximum >5,000 IU/ml), peripheral eosinophilia, defective B cell memory, and impaired acute-phase responses (PMID: 28747427). Shahin et al. (2019) then identified another homozygous missense (p.P498L) mutation in a son of consanguineous Turkish parents with recurrent otitis media, bilateral keratitis, recurrent and often complicated respiratory infections, as well as severe atopies and significant musculoskeletal anomalies including scaphocephaly, progressive thoracolumbar scoliosis and destructive arthropathy (PMID: 30309848). The authors found that this variant abrogated GP130 signaling in response to IL-6 and IL-27 in PBMCs and IL-6 and IL-11 in fibroblasts. They further showed that loss of IL-6 signaling led to aberrant development of CCR6-expressing memory CD4+ and CD8+ T cells. Finally, they showed that P498L led to more severe loss of IL-27 responses, and consequently more dramatic loss of Th1 polarization, compared to N404Y. Chen et al. (2021), reported an 8-year-old boy of mixed ethnic origin who was compound heterozygous for the following mutations in the IL6ST gene: p.A517P and a splice site mutation resulting in exon skipping null variant p.G484_P518delinsR. The boy presented a typical clinical presentation of AR-HIES. The authors discuss the 3 cases reported so far with AR-HIES due to mutations in IL6ST (HIES4B). All 3 patients presented with a similar phenotype characteriyed by high IgE level, recurrent bacterial infections, skeletal abnormalities and retained teeth. Two carry homozygous variants p.Asn404Tyr and p.Pro498Leu, and one carries compound heterozygous for p.Ala517Pro and the exon skipping null variant p.Gly484_Pro518delinsArg. Functional studies on the missense variants showed that they disrupt the GP130 dimeric interaction with the IL6 and IL11 receptor complex, but not the trimeric LIF receptor complex (GP130, LIF and LIFR) (PMID: 33771552). While homozygous missense variants in IL6ST present with a partial cytokine defect (complete loss of IL6 and IL11, a partial to severe loss of IL27 and OSM, partial loss to normal LIF signaling) and phenotype of HIES4B, complete loss of function variants in IL6ST cause an expanded form of Stuve Wiedemann syndrome (PMID: 31914175). Chen et al. (2020) have also identified recurrent homozygous loss-of-function (LOF) variants (p.R281X and c.1699+4A>G) associated with a lethal Stüve-Wiedemann–like skeletal phenotype characterized by skeletal dysplasia and neonatal lung dysfunction with additional syndromic features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase responses. The two identified variants are associated with complete loss of GP130-dependent IL-6, IL-11, IL-27, OSM, and LIF signaling (PMID: 31914175). More recently, monoallelic dominant-negative mutations in IL6ST have been reported to underlie a novel form of AD-HIES (PMID: 32207811). Beziat et [Load More]