Alternative titles; symbols
HGNC Approved Gene Symbol: IL6ST
Cytogenetic location: 5q11.2 Genomic coordinates (GRCh38): 5:55,935,095-55,994,963 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q11.2 | ?Immunodeficiency 94 with autoinflammation and dysmorphic facies | 619750 | Autosomal dominant | 3 |
| Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections | 619752 | Autosomal dominant | 3 | |
| Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections | 618523 | Autosomal recessive | 3 | |
| Stuve-Wiedemann syndrome 2 | 619751 | Autosomal recessive | 3 |
Initially described as the interleukin-6 signal transducer, gp130 is a transducer chain shared by many cytokines, including IL6 (147620), IL11 (147681), leukemia inhibitory factor (LIF; 159540), oncostatin M (OSM; 165095), and ciliary neurotrophic factor (CNTF; 118945), as reviewed by Kishimoto et al. (1994). All of these cytokines act via a bi- or tripartite receptor complex in which signaling is triggered by homodimerization (IL6) or heterodimerization with LIF-Rb/gp190 protein (IL11, LIF, OSM, and CNTF) of gp130. These cytokines thus mediate similar biologic activities in various tissues. See also IL6RA (147880).
By immunoscreening a placenta cDNA expression library with antibodies to human gp130, followed by screening a myeloma cell line cDNA library, Hibi et al. (1990) cloned gp130. The deduced 918-amino acid protein has an N-terminal signal peptide, followed by a 597-amino acid extracellular region, a transmembrane domain, and a 277-amino acid cytoplasmic domain. It also contains 14 potential N-glycosylation sites. The mature 896-amino acid protein has a calculated molecular mass of 101 kD. Part of the extracellular region, including 4 conserved cysteines and a WSxWS motif, shows significant homology with cytokine receptors. Gp130 is most closely related to GCSFR (CSF3R; 138971). Both receptors contain 6 fibronectin (135600) type III modules in the extracellular region. The intracellular domain has a consensus nucleotide-binding domain, but it has no protein kinase catalytic domain. Four sequences in the intracellular domain are similar to GTP-binding motifs of RAS (190020)-related proteins. Northern blot analysis detected a 7.0-kb transcript in all cell lines examined. Gp130 showed an apparent molecular mass of 130 kD by SDS-PAGE.
Saito et al. (1992) cloned mouse gp130. The deduced 917-amino acid protein has a domain structure equivalent to that of human gp130, including 4 conserved cysteines and the 4 GTP-binding motif-like sequences. Mouse and human gp130 share 76.8% amino acid homology, including 100% identity in a 116-amino acid stretch that spans the transmembrane domain. Northern blot analysis detected 7.0- and 10.0-kb transcripts expressed in varying ratios in all tissues examined. Lowest expression was in spleen. During mouse embryonic development, robust expression of both gp130 transcripts was detected on day 6, and expression peaked on day 8.
Narazaki et al. (1993) purified 2 soluble forms of gp130 (sgp130) from human serum. These proteins had apparent molecular masses of 90 and 110 kD.
Diamant et al. (1997) cloned sgp130 from a peripheral blood mononuclear cell cDNA library. The deduced protein contains 624 amino acids. Diamant et al. (1997) determined that the sgp130 transcript results from alternative splicing and includes an 85-bp exon just before the transmembrane-coding exon. This insertion results in a frameshift, and the sequence following the insertion encodes 4 amino acids not found in full-length membrane-bound gp130, followed by a stop codon 1 bp from the transmembrane-coding region. PCR analysis detected expression of sgp130 in all myeloma cell lines tested except 1 line growing independent of IL6 stimulation. Chinese hamster ovary (CHO) cells transfected with sgp130 secreted the protein into the medium. Some sgp130 was also secreted by CHO cells transfected with cDNA encoding full-length gp130, but at a much lower concentration. Diamant et al. (1997) concluded that sgp130 could be generated both by shedding and by expressing an alternatively spliced transcript.
Szalai et al. (2000) determined that the IL6ST gene contains 17 exons and spans about 51 kb.
By fluorescence in situ hybridization, Rodriguez et al. (1995) assigned the functional IL6ST gene to chromosome 5q11 and its nontranscribed pseudogene to 17p11.
Hartz (2010) mapped the IL6ST gene to chromosome 5q11.2 based on an alignment of the IL6ST sequence (GenBank AB015706) with the genomic sequence (GRCh37).
Pseudogenes
Kidd et al. (1992) concluded that there are 2 functional genes for IL6ST. Rodriguez et al. (1995) showed, however, that the 2 localizations correspond to a pseudogene (on chromosome 17) and the functional gene on chromosome 5.
Hibi et al. (1990) determined that cells transfected with IL6RA (147880) expressed mainly low-affinity IL6-binding sites. Cotransfection of gp130 cDNA increased the number of high-affinity binding sites, but gp130 did not directly bind IL6 (147620) or several other cytokines. Mouse IL3 (147740)-dependent pre-B cells proliferated when cultured with IL6 plus soluble IL6RA only following transfection with human gp130. Hibi et al. (1990) concluded that gp130 is involved in the formation of high-affinity IL6-binding sites and in IL6 signal transduction.
Murakami et al. (1991) analyzed C-terminal truncation mutants of gp130. Mutants retaining only the last 10 amino acids of the 277-amino acid C-terminal region proximal to the transmembrane domain were capable of binding the IL6/IL6R complex; however, these mutants were unable to transduce the growth signal following IL6/IL6R complex binding. Signal transduction required a 61-amino acid region containing 2 short segments that share homology with other cytokine receptor family members. Gp130 molecules with mutations in either of these segments could not transduce a growth signal. Loss of signal-transducing ability coincided with loss of IL6-induced tyrosine phosphorylation of gp130.
Saito et al. (1992) determined that administration of IL6 in mice caused upregulation of gp130 mRNA in several tissues. In liver, both gp130 and Il6ra mRNA were upregulated by IL6.
Narazaki et al. (1993) determined that sgp130 within human serum or exogenous recombinant sgp130 inhibited growth of transfected mouse pre-B cells induced by the IL6/IL6R complex. Recombinant sgp130 also inhibited growth in erythroleukemia cells stimulated by OSM or the CNTF/CNTFR (118946) complex in a dose-dependent manner. Recombinant sgp130 was less inhibitory to growth induced by LIF or the IL6/IL6R complex. Narazaki et al. (1993) concluded that sgp130 has a role in modulating signals transduced by membrane-bound gp130.
Chow et al. (2001) noted that cytokines that activate gp130 share a common 4-helix bundle fold and that gp130 recognition of ligands occurs through its cytokine-binding homology region, located at domains 2 and 3. In addition, activation occurs through a separate N-terminal, Ig-like domain (domain 1). Kaposi sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a functional homolog of IL6 (termed vIL6; 25% sequence homology) that is expressed in KSHV-infected cells and is able to induce angiogenesis and hematopoiesis in IL6-dependent cell lines. In contrast to IL6, which binds to gp130 only after it forms a complex with IL6RA, vIL6 directly activates gp130. By crystal structure analysis, Chow et al. (2001) demonstrated that in the extracellular signaling assembly between vIL6 and gp130, 2 complexes are cross-linked into a tetramer through direct interactions between the Ig domain of gp130 and site III of vIL6, which is necessary for gp130 activation. Unlike IL6, vIL6 uses mainly hydrophobic residues to contact gp130, enhancing the complementarity of the vIL6-gp130 binding interfaces. Identical positions of 2 disulfide bonds in IL6 and vIL6 and the high conservation of the hydrophobic core residues account for the reproduction of the helical scaffold by vIL6, enabling gp130 contact.
Pflanz et al. (2004) found that transfection of WSX1 (605350) into a cell line expressing gp130 but only low levels of WSX1 resulted in IL27 (see 605816)-dependent phosphorylation of STAT1 (600555) and STAT3 (102582). In addition, they showed that anti-gp130 blocked IL27-mediated cellular effects. Quantitative PCR analysis indicated that, in addition to naive CD4 (186940)-positive T cells, numerous cell types expressed both gp130 and WSX1, including mast cells. IL27 stimulation of mast cells resulted in upregulation of proinflammatory cytokine expression. Pflanz et al. (2004) concluded that IL27 not only contributes to the development of an adaptive immune response through its action on CD4-positive T cells, but also directly acts on cells of the innate immune system.
Taniguchi et al. (2015) showed in mice and human cells that GP130, a coreceptor for IL6 cytokines, triggers activation of YAP (606608) and Notch (190198), transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3. Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC (190090) and YES (164880), 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.
Crystal Structure
IL6 is an immunoregulatory cytokine that activates a cell-surface signaling assembly composed of IL6, IL6RA, and the shared signaling receptor gp130. Boulanger et al. (2003) solved the crystal structure of the extracellular signaling complex to 3.65-angstrom resolution, which revealed a hexameric, interlocking assembly mediated by a total of 10 symmetry-related, thermodynamically coupled interfaces. Assembly of the hexameric complex occurs sequentially: IL6 is first engaged by IL6R-alpha and then presented to gp130 in the proper geometry to facilitate a cooperative transition into the high affinity, signaling-competent hexamer. The quaternary structures of other IL6/IL12 family signaling complexes are likely constructed by means of a similar topologic blueprint.
Hyper-IgE Syndrome 4B, Autosomal Recessive, with Recurrent Infections
In a girl, born of consanguineous parents of South Asian descent, with autosomal recessive hyper-IgE syndrome-4B with recurrent infections (HIES4B; 618523), Schwerd et al. (2017) identified a homozygous missense mutation in the IL6ST gene (N404Y; 600694.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived cells showed a complete loss of STAT3 response to IL6 stimulation compared to controls; these defects were rescued by expression of wildtype GP130. Knockdown of GP130 in HEK293 cells using CRISPR/Cas9 technology showed that mutant cells did not phosphorylate STAT1 or STAT3 in response to stimulation with the known ligands IL6, IL11, IL27, OSM, or LIF, but did respond to stimulation with interferon. GP130-null cells transfected with the mutation showed absent response to IL11 stimulation and decreased response to IL6, IL27, and OSM; LIF response was largely intact. Transfection of wildtype GP130 rescued the defect. In vitro functional expression studies in GP130-null human hepatoma cells showed a defective IL6-mediated acute-phase response. The findings were consistent with a loss of function and impaired IL6ST-mediated downstream signaling. Direct sequencing of the IL6ST gene in over 400 patients with craniosynostosis and over 200 patients with HIES did not identify any pathogenic variants.
In a boy, born of consanguineous Turkish parents, with HIES4B, Shahin et al. (2019) identified a homozygous missense mutation in the IL6ST gene (P498L; 600694.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional studies of patient-derived cells and HEK293 cells transfected with the mutation showed impaired STAT3 response particularly to IL6, IL11, and IL27, compared to controls. These defects could be rescued by expression of wildtype IL6ST. The effects were apparent in both B- and T-cell subsets, as well as in fibroblasts. The findings were consistent with a loss-of-function effect and variably impaired downstream IL6ST signaling.
In an 8-year-old boy with HIES4B, Chen et al. (2021) identified compound heterozygous mutations in the IL6ST gene: A517P (600694.0010) and a splice site mutation resulting in a null allele (600694.0011). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, occurred in trans. Patient fibroblasts showed impaired IL6, IL11, and OSM signaling compared to controls. In vitro functional expression studies in HEK293 cells transfected with the A517P mutation showed that the mutant protein was expressed at the plasma membrane, but a large amount was also present in the endoplasmic reticulum and in endosomes, suggesting delayed protein maturation and trafficking. There was defective phosphorylation of STAT3 in response to IL6ST-dependent cytokines. The authors provided a structural model to explain the cytokine selectivity resulting from the missense mutation.
Hyper-IgE Syndrome 4A, Autosomal Dominant, with Recurrent Infections
In 11 patients from 8 unrelated families of various ethnic origins with autosomal dominant hyper-IgE syndrome-4A with recurrent infections (HIES4A; 619752), Beziat et al. (2020) identified 7 different heterozygous truncating mutations in the IL6ST gene (see, e.g., 600694.0006-600694.0009). The mutations, which were found by targeted sequencing or whole-exome sequencing and confirmed by Sanger sequencing, were all absent from the gnomAD database. The mutations segregated with the disorder in 2 families; the mutations occurred de novo in the other patients. The mutations occurred in the intracellular C-terminal region and the mutant alleles encoded GP130 receptors bearing the transmembrane domain, but lacking both the recycling motif and all 4 STAT3-recruiting tyrosine residues. In vitro cellular expression studies in HEK293 cells showed that the recombinant mutant IL6ST proteins accumulated abnormally at the cell surface and interfered with wildtype function in a dominant-negative manner. The mutant alleles were unable to restore STAT3 phosphorylation upon IL6 stimulation in IL6ST-null cells, and cellular responses to IL6, IL11, LIF (159540), and OSM (165095) were severely impaired compared to controls. Fibroblasts derived from patients with more severe skeletal phenotypes had impaired STAT3 phosphorylation in response to IL11 stimulation compared to controls, whereas this effect was less pronounced in fibroblasts from patients with milder skeletal phenotypes.
Stuve-Wiedemann Syndrome 2
In 5 patients from 3 unrelated families with a lethal form of Stuve-Wiedemann syndrome (STWS2; 619751), Chen et al. (2020) identified homozygosity for mutations in the IL6ST gene: a nonsense mutation (R281X; 600694.0003) was present in 2 sibs each from a consanguineous Afghan family and in 2 sibs from a consanguineous Saudi family, and a splice site mutation (600694.0004) was found in an affected Dutch girl. Functional analysis demonstrated reduced or absent surface expression of GP130, and there was complete absence of signaling by the IL6 cytokine family, including LIF (159540).
Immunodeficiency 94 with Autoinflammation and Dysmorphic Facies
In a 12-year-old boy with immunodeficiency-94 with autoinflammation and dysmorphic facies (IMD94; 619750), Materna-Kiryluk et al. (2021) identified a de novo heterozygous in-frame deletion in the IL6ST gene (c.560_571del; 600694.0005). The mutation, which was found by whole-exome sequencing and confirmed by deep sequencing, was not present in the gnomAD database. The mutation in the patient appeared as a mosaic, with 10% of reads showing the variant. Immortalized patient-derived B cells, of which 95% expressed the mutation, showed constitutive STAT3 (102582) hyperphosphorylation, indicating persistent IL6R signaling in the absence of ligand. Treatment of the cells with the JAK inhibitors tofacitinib and ruxolitinib significantly reduced the STAT3 phosphorylation in vitro. These findings were consistent with a gain-of-function effect. The authors noted that this same mutation in the somatic state is a recurrent cause of inflammatory hepatocellular tumors with associated systemic amyloidosis (see Rebouissou et al., 2009). However, aside from hepatosplenomegaly, the patient with IMD94 did not have evidence of hepatic tumors or amyloidosis.
Somatic Mutations
Rebouissou et al. (2009) demonstrated a marked activation of the IL6 (147620) signaling pathway in inflammatory hepatocellular adenomas. Sequencing candidate genes pinpointed the response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signaling coreceptor gp130. Rebouissou et al. (2009) found that 60% of inflammatory hepatocellular adenomas harbor small in-frame deletions that target the binding sites of gp130 for IL6, and expression of 4 different gp130 mutants in hepatocellular cells activated STAT3 (102582) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by beta-catenin (116806)-activating mutations, suggesting a cooperative effect of these signaling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumorous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumors with STAT activation.
Using Cre-loxP-mediated recombination to generate mice harboring a ventricular-restricted knockout of the gp130 cytokine receptor, Hirota et al. (1999) demonstrated a critical role for a gp130-dependent myocyte survival pathway in the transition to heart failure. Such conditional mutant mice have normal cardiac structure and function, but during aortic pressure overload, these mice displayed rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis compared with the control mice, which exhibited compensatory hypertrophy. Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. Hirota et al. (1999) suggested that gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure.
Tebbutt et al. (2002) noted that gp130 contains at least 2 cell-signaling modules. One encompasses 4 phosphotyrosine-binding sites for the SH2 domains of STAT1 and STAT3, whereas the other includes a phosphotyrosine that activates SHP2 (176876) upstream of the RAS (190020)-ERK (see 601795) pathway. Tebbutt et al. (2002) generated mice carrying targeted mutations in each of these modules. Mice homozygous for a truncated version of gp130 lacking all Stat-binding sites spontaneously developed intestinal ulceration at sites associated with repeated mechanical trauma (gastric pylorus and rectum). Unlike wildtype mice, those with the Stat-binding domain mutation were unable to recover from trauma induced by ingestion of sodium dextran sulfate. Tebbutt et al. (2002) noted that impaired wound healing occurs in Tff3 (600633)-null mice, and biochemical analysis confirmed reduced levels of Tff3 in the mice with the Stat-binding domain mutation. Mice homozygous for a tyr757-to-phe (Y757F) mutation, which inactivated the Shp2-binding domain of gp130, developed normally into superficially healthy adults, but they showed age-dependent enlargement of the stomach, proximal small intestine, and spleen. Histologic examination revealed hyperproliferative lesions within the antropyloric mucosa, often circumferential, resulting in gastric outlet obstruction. Tebbutt et al. (2002) noted that the gastric pathology was essentially phenocopied in Tff1 (113710) null mice, and biochemical analysis of gastric Tff1 levels in mice with the Shp2-binding domain mutation confirmed a 75% reduction in comparison with wildtype mice; levels of Tff3 were elevated in the mutant mice. Using a luciferase reporter assay with cells transiently transfected with gp130 carrying the Stat- and Shp2-binding domain mutations, Tebbutt et al. (2002) confirmed simultaneous activation of the Stat1/Stat3 and Shp2-Ras-Erk pathways in response to IL6 activation, resulting in enhanced luciferase activity of Tff1-luc and Tff3-luc reporter constructs. Tebbutt et al. (2002) concluded that the pathologies observed in the gp130 mutant mice resulted from disruption of the normally simultaneous and coordinated activation of the Stat1/Stat3 and Shp2-Ras-Erk signaling cascades.
Atsumi et al. (2002) generated mice with a tyr759-to-phe mutation in the Shp2-binding site of gp130. These mice developed a rheumatoid arthritis (RA; 180300)-like joint disease at about 1 year of age, accompanied by autoantibody production and accumulation of memory/activated T cells and myeloid cells. Before disease onset, T cells were hyperresponsive in vitro. Mutant mice that were also Rag2 (179616) deficient did not develop disease, indicating the importance of lymphocytes in this model. Atsumi et al. (2002) concluded that point mutation in the gp130 cytokine receptor can induce autoimmune disease.
Jenkins et al. (2005) assessed the contribution of exaggerated Stat3 activation to the phenotype of mice homozygous for Y757F, which disrupts the negative feedback mechanism on gp130-dependent Stat signaling (Tebbutt et al., 2002). They found that development of abnormalities associated with gp130(Y757F) homozygosity, including reduced life span, splenomegaly, exaggerated hepatic acute-phase response, and spontaneous gastric adenomas while young, was attenuated when gp130(Y757F) homozygosity was expressed on a Stat3 +/- background.
Both bone formation and resorption are altered significantly in gp130 -/- mice. Although the mutation results in neonatal lethality, reduced trabecular bone mass, associated with an increase in osteoclastogenesis, is a feature of the neonatal skeleton (Kawasaki et al., 1997; Shin et al., 2004). Sims et al. (2004) found that mouse strains homozygous for gp130 mutations in the Stat activation sites had normal trabecular bone volume and bone turnover, but reduced bone length and premature growth plate closure, suggesting a role for gp130-STAT1/3 signaling in chondrocyte differentiation. In contrast, mice with mutations in the gp130 Shp2-Ras-Mapk (see 176948) activation sites showed normal bone size, but reduced trabecular bone volume and high bone turnover, associated with increased osteoclastogenesis. Sims et al. (2004) concluded that gp130 controls balanced regulation of bone growth and mass depending on selective activation of distinct downstream signaling pathways.
In a girl, born of consanguineous parents of South Asian descent, with autosomal recessive hyper-IgE syndrome-4B with recurrent infections (HIES4B; 618523), Schwerd et al. (2017) identified a homozygous c.1210A-T transversion (c.1210A-T, NM_002184) in the IL6ST gene, resulting in an asn404-to-tyr (N404Y) substitution at a highly conserved residue in the fourth fibronectin type III domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the EVS, 1000 Genomes Project, ExAC, or gnomAD databases. Detailed functional expression studies in patient cells and HEK293 cells showed that the mutation caused impaired IL6ST-mediated downstream signaling, consistent with a loss of function.
In a boy, born of consanguineous Turkish parents, with autosomal recessive hyper-IgE syndrome-4B with recurrent infections (HIES4B; 618523), Shahin et al. (2019) identified a homozygous c.1493C-T transition in the IL6ST gene, resulting in a pro498-to-leu (P498L) substitution at a highly conserved residue in the fifth fibronectin type III domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP or ExAC database. Detailed functional expression studies in patient cells and HEK293 cells showed that the mutation caused impaired IL6ST-mediated downstream signaling, consistent with a loss of function.
In 2 Afghan sibs (family A) and 2 Saudi sibs (family B) with Stuve-Wiedemann syndrome-2 (STWS2; 619751), Chen et al. (2020) identified homozygosity for a c.841C-T transition (c.841C-T, NM_002184.3) in the IL6ST gene, resulting in an arg281-to-ter (R281X) substitution that was predicted to delete the membrane-binding region. The unaffected consanguineous parents from both families were heterozygous for the mutation, which was not found in an in-house database of 1,432 individuals or in the 1000 Genomes Project or gnomAD databases. Analysis of SNP data and regions of homozygosity in the 2 families suggested that they were not related. Expression of GP130 was absent from femur sections from the Afghan fetus (A-II-1) as well as from the surface of patient-derived amniocytes. Studies in transfected HEK293 cells confirmed absent surface expression of mutant GP130. In addition, in HEK293 cells transfected with the R281X mutant, the GP130 effector STAT3 (102582) was unresponsive to GP130-dependent cytokines. Similarly, patient-derived amniocytes consistently displayed a complete loss of STAT3 signaling upon stimulation with GP130-dependent cytokines, and transduction of wildtype GP130 resulted in partial rescue.
In a Dutch girl (family C) who died at age 6 years with Stuve-Wiedemann syndrome-2 (STWS2; 619751), Chen et al. (2020) identified homozygosity for a splice site mutation (c.1699+4A-G, NM_002184.3) in intron 13 of the IL6ST gene. A similarly affected older brother had died at 2 days after birth due to respiratory failure. The family was lost to follow-up, and thus parental DNA was unavailable for analysis. No variation at that highly conserved splice site was found in in-house databases or in the 1000 Genomes Project or gnomAD databases. Analysis of mRNA in EBV-transformed lymphoblastoid cell lines from the proband showed that expression of exons 12 and 13 was absent, and skipping of exon 13 was confirmed by sequencing of cDNA. GP130 was present on the surface of patient cells, but with a 20 to 30% reduction compared to control cells. HEK293 cells transfected with the c.1699+4A-G mutant also showed detectable but reduced surface GP130, and the cells did not respond to GP130-dependent cytokines. The authors concluded that the splicing variant results in a truncated extracellular GP130 receptor that is expressed but nonfunctional.
In a 12-year-old boy with immunodeficiency-94 with autoinflammation and dysmorphic facies (IMD94; 619750), Materna-Kiryluk et al. (2021) identified a de novo heterozygous 12-bp in-frame deletion in the IL6ST gene (c.560_571del, NM_002184.4), resulting in the deletion of 4 amino acids (Ser187_Tyr190del) within the IL6-binding site. The mutation, which was found by whole-exome sequencing and confirmed by deep sequencing, was not present in the gnomAD database. The mutation in the patient appeared as a mosaic, with 10% of reads showing the variant. Immortalized patient-derived B cells, of which 95% expressed the mutation, showed constitutive STAT3 (102582) hyperphosphorylation, indicating persistent IL6R signaling in the absence of ligand. Treatment of the cells with the JAK inhibitors tofacitinib and ruxolitinib significantly reduced the STAT3 phosphorylation in vitro. These findings were consistent with a gain-of-function effect. The patient presented in the first months of life with lymphadenopathy, features of autoinflammation, and immunodeficiency with hypogammaglobulinemia. Intellectual development was normal and serum IgE was not elevated. The authors noted that this same mutation in the somatic state is a recurrent cause of inflammatory hepatocellular tumors with associated systemic amyloidosis (see Rebouissou et al., 2009). However, aside from hepatosplenomegaly, the patient with IMD94 did not have evidence of hepatic tumors or amyloidosis.
In 3 patients spanning 3 generations of a family (P2-P4 from kindred A) with autosomal dominant hyper-IgE syndrome-4A with recurrent infections (HIES4A; 619752), Beziat et al. (2020), identified a heterozygous 5-bp duplication (c.2277_2281dup) in the IL6ST gene, resulting in a frameshift and premature termination (Thr761fsTer29). The mutation, which was found by targeted sequencing in some patients and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation segregated with the disorder in the family. In vitro cellular expression studies in HEK293 cells showed that the recombinant mutant IL6ST protein accumulated abnormally at the cell surface and interfered with wildtype function in a dominant-negative manner.
In 3 patients from 2 unrelated families (kindreds B and C) with autosomal dominant hyper-IgE syndrome-4A with recurrent infections (HIES4A; 619752), Beziat et al. (2020) identified a heterozygous 1-bp duplication (c.2155dup) in the IL6ST gene, resulting in a frameshift and premature termination (Ile719AsnfsTer2). The mutation, which was found by targeted sequencing or whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation occurred de novo in P5 from kindred B and segregated with the disorder in the 2 patients (P6 and P7) from kindred C. In vitro cellular expression studies in HEK293 cells showed that the recombinant mutant IL6ST protein accumulated abnormally at the cell surface and interfered with wildtype function in a dominant-negative manner.
In a 27-year-old woman (P9 from kindred E) who died from complications of autosomal dominant hyper-IgE syndrome-4A with recurrent infections (HIES4A; 619752), Beziat et al. (2020) identified a de novo heterozygous 1-bp deletion (c.2121del), resulting in a frameshift and premature termination (Leu708Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro cellular expression studies in HEK293 cells showed that the recombinant mutant IL6ST protein accumulated abnormally at the cell surface and interfered with wildtype function in a dominant-negative manner.
In a 22-year-old woman (P10 from kindred F) who died from complications of autosomal dominant hyper-IgE syndrome-4A with recurrent infections (HIES4A; 619752), Beziat et al. (2020) identified a de novo heterozygous c.2277T-G transversion in the IL6ST gene, resulting in a tyr759-to-ter (Y750X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro cellular expression studies in HEK293 cells showed that the recombinant mutant IL6ST protein accumulated abnormally at the cell surface and interfered with wildtype function in a dominant-negative manner.
In an 8-year-old boy with autosomal recessive hyper-IgE syndrome-4B with recurrent infections (HIES4B; 618523), Chen et al. (2021) identified compound heterozygous mutations in the IL6ST gene: a c.1549G-C transversion (c.1549G-C, NM_002184.3), resulting in an ala517-to-pro (A517P) substitution, and an A-to-C transversion (c.1552+3A-C; 600694.0011), resulting in a splicing defect, the skipping of exon 12, and an in-frame del/ins (Gly484_Pro518delinsArg). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, occurred in trans. The splice site mutation was shown to be inherited from the unaffected mother; DNA from the father was unavailable. A517P was found in 2 of 280,866 alleles in the gnomAD database, whereas the splice site mutation was not present in gnomAD. The splice variant was not expressed and was determined to be a null allele. Patient fibroblasts showed impaired IL6, IL11, and OSM signaling compared to controls. In vitro functional expression studies in HEK293 cells transfected with the A517P mutation showed that the mutant protein was expressed at the plasma membrane, but a large amount was also present in the endoplasmic reticulum and in endosomes, suggesting delayed protein maturation and trafficking. There was defective phosphorylation of STAT3 in response to IL6ST-dependent cytokines. The authors provided a structural model to explain the cytokine selectivity resulting from the missense mutation.
For discussion of the A-to-C transversion at the donor site of intron 12 (c.1552+3A-C, NM_002184.3) of the IL6ST gene, resulting in a splicing defect, skipping of exon 12, and an in-frame del/ins (Gly484_Pro518delinsArg), that was found in compound heterozygous state in a patient with autosomal recessive hyper-IgE syndrome-4B with recurrent infections (HIES4B; 618523) by Chen et al. (2021), see 600694.0010.
Atsumi, T., Ishihara, K., Kamimura, D., Ikushima, H., Ohtani, T., Hirota, S., Kobayashi, H., Park, S.-J., Saeki, Y., Kitamura, Y., Hirano, T. A point mutation of tyr-759 in interleukin 6 family cytokine receptor gp130 causes autoimmune arthritis. J. Exp. Med. 196: 979-990, 2002. [PubMed: 12370259] [Full Text: https://doi.org/10.1084/jem.20020619]
Beziat, V., Tavernier, S. J., Chen, Y.-H., Ma, C. S., Materna, M., Laurence, A., Staal, J., Aschenbrenner, D., Roels, L., Worley, L., Claes, K., Gartner, L., and 48 others. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J. Exp. Med. 217: e20191804, 2020. Note: Erratum: J. Exp. Med. 217: e2019180405272020c, 2020. [PubMed: 32207811] [Full Text: https://doi.org/10.1084/jem.20191804]
Boulanger, M. J., Chow, D., Brevnova, E. E., Garcia, K. C. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301: 918 only, 2003. [PubMed: 12829785] [Full Text: https://doi.org/10.1126/science.1083901]
Chen, Y.-H., Grigelioniene, G., Newton, P. T., Gullander, J., Elfving, M., Hammarsjo, A., Batkovskyte, D., Alsaif, H. S., Kurdi, W. I. Y., Abdulwahab, F., Shanmugasundaram, V., Devey, L., and 15 others. Absence of GP130 cytokine receptor signaling causes extended Stuve-Wiedemann syndrome. J. Exp. Med. 217: e20191306, 2020. [PubMed: 31914175] [Full Text: https://doi.org/10.1084/jem.20191306]
Chen, Y.-H., Zastrow, D. B., Metcalfe, R. D., Gartner, L., Krause, F., Morton, C. J., Marwaha, S., Fresard, L., Huang, Y., Zhao, C., McCormack, C., Bick, D., and 16 others. Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome. J. Allergy Clin. Immun. 148: 585-598, 2021. [PubMed: 33771552] [Full Text: https://doi.org/10.1016/j.jaci.2021.02.044]
Chow, D., He, X., Snow, A. L., Rose-John, S., Garcia, K. C. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291: 2150-2155, 2001. [PubMed: 11251120] [Full Text: https://doi.org/10.1126/science.1058308]
Diamant, M., Rieneck, K., Mechti, N., Zhang, X.-G., Svenson, M., Bendtzen, K., Klein, B. Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin-6 signal transducer gp130. FEBS Lett. 412: 379-384, 1997. [PubMed: 9256256] [Full Text: https://doi.org/10.1016/s0014-5793(97)00750-3]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/22/2010.
Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T., Kishimoto, T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63: 1149-1157, 1990. [PubMed: 2261637] [Full Text: https://doi.org/10.1016/0092-8674(90)90411-7]
Hirota, H., Chen, J., Betz, U. A. K., Rajewsky, K., Gu, Y., Ross, J., Jr., Muller, W., Chien, K. R. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biochemical stress. Cell 97: 189-198, 1999. [PubMed: 10219240] [Full Text: https://doi.org/10.1016/s0092-8674(00)80729-1]
Jenkins, B. J., Grail, D., Nheu, T., Najkovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R. M., Jones, S. A., Topley, N., Baumann, H., Judd, L. M., Giraud, A. S., Boussioutas, A., Zhu, H.-J., Ernst, M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nature Med. 11: 845-852, 2005. [PubMed: 16041381] [Full Text: https://doi.org/10.1038/nm1282]
Kawasaki, K., Gao, Y.-H., Yokose, S., Kaji, Y., Nakamura, T., Suda, T., Yoshida, K., Taga, T., Kishimoto, T., Kataoka, H., Yuasa, T., Norimatsu, H., Yamaguchi, A. Osteoclasts are present in gp130-deficient mice. Endocrinology 138: 4959-4965, 1997. [PubMed: 9348227] [Full Text: https://doi.org/10.1210/endo.138.11.5534]
Kidd, V. J., Nesbitt, J. E., Fuller, G. M. Chromosomal localization of the IL-6 receptor signal transducing subunit, gp130 (IL6ST). Somat. Cell Molec. Genet. 18: 477-483, 1992. [PubMed: 1475713] [Full Text: https://doi.org/10.1007/BF01233087]
Kishimoto, T., Taga, T., Akira, S. Cytokine signal transduction. Cell 76: 253-262, 1994. [PubMed: 8293462] [Full Text: https://doi.org/10.1016/0092-8674(94)90333-6]
Materna-Kiryluk, A., Pollak, A., Gawalski, K., Szczawinska-Poplonyk, A., Rydzynska, Z., Sosnowska, A., Cukrowska, B., Gasperowicz, P., Konopka, E., Pietrucha, B., Grzywa, T. M., Banaszak-Ziemska, M., Niedziela, M., Skalska-Sadowska, J., Stawinski, P., Sladowski, D., Nowis, D., Ploski, R. Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy. Hum. Molec. Genet. 30: 226-233, 2021. [PubMed: 33517393] [Full Text: https://doi.org/10.1093/hmg/ddab035]
Murakami, M., Narazaki, M., Hibi, M., Yawata, H., Yasukawa, K., Hamaguchi, M., Taga, T., Kishimoto, T. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc. Nat. Acad. Sci. 88: 11349-11353, 1991. [PubMed: 1662392] [Full Text: https://doi.org/10.1073/pnas.88.24.11349]
Narazaki, M., Yasukawa, K., Saito, T., Ohsugi, Y., Fukui, H., Koishihara, Y., Yancopoulos, G. D., Taga, T., Kishimoto, T. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 82: 1120-1126, 1993. [PubMed: 8353278]
Pflanz, S., Hibbert, L., Mattson, J., Rosales, R., Vaisberg, E., Bazan, J. F., Phillips, J. H., McClanahan, T. K., de Waal Malefyt, R., Kastelein, R. A. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immun. 172: 2225-2231, 2004. [PubMed: 14764690] [Full Text: https://doi.org/10.4049/jimmunol.172.4.2225]
Rebouissou, S., Amessou, M., Couchy, G., Poussin, K., Imbeaud, S., Pilati, C., Izard, T., Balabaud, C., Bioulac-Sage, P., Zucman-Rossi, J. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457: 200-204, 2009. [PubMed: 19020503] [Full Text: https://doi.org/10.1038/nature07475]
Rodriguez, C., Grosgeorge, J., Nguyen, V. C., Gaudray, P., Theillet, C. Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11. Cytogenet. Cell Genet. 70: 64-67, 1995. [PubMed: 7736792] [Full Text: https://doi.org/10.1159/000133993]
Saito, M., Yoshida, K., Hibi, M., Taga, T., Kishimoto, T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J. Immun. 148: 4066-4071, 1992. [PubMed: 1602143]
Schwerd, T., Twigg, S. R. F., Aschenbrenner, D., Manrique, S., Miller, K. A., Taylor, I. B., Capitani, M., McGowan, S. J., Sweeney, E., Weber, A., Chen, L., Bowness, P., and 13 others. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J. Exp. Med. 214: 2547-2562, 2017. [PubMed: 28747427] [Full Text: https://doi.org/10.1084/jem.20161810]
Shahin, T., Aschenbrenner, D., Cagdas, D., Bal, S. K., Conde, C. D., Garncarz, W., Medgyesi, D., Schwerd, T., Karaatmaca, B., Cetinkaya, P. G., Esenboga, S., Twigg, S. R. F., Cant, A., Wilkie, A. O. M., Tezcan, I., Uhlig, H. H., Boztug, K. Selective loss of function variants in IL6ST cause hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 104: 609-621, 2019. [PubMed: 30309848] [Full Text: https://doi.org/10.3324/haematol.2018.194233]
Shin, H.-I., Divieti, P., Sims, N. A., Kobayashi, T., Miao, D., Karaplis, A. C., Baron, R., Bringhurst, R., Kronenberg, H. M. gp130-mediated signaling is necessary for normal osteoblastic function in vivo and in vitro. Endocrinology 145: 1376-1385, 2004. [PubMed: 14617570] [Full Text: https://doi.org/10.1210/en.2003-0839]
Sims, N. A., Jenkins, B. J., Quinn, J. M. W., Nakamura, A., Glatt, M., Gillespie, M. T., Ernst, M., Martin, T. J. Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J. Clin. Invest. 113: 379-389, 2004. [PubMed: 14755335] [Full Text: https://doi.org/10.1172/JCI19872]
Szalai, C., Toth, S., Falus, A. Exon-intron organization of the human gp130 gene. Gene 243: 161-166, 2000. [PubMed: 10675624] [Full Text: https://doi.org/10.1016/s0378-1119(99)00536-3]
Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519: 57-62, 2015. [PubMed: 25731159] [Full Text: https://doi.org/10.1038/nature14228]
Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., Heath, J. K., Ernst, M. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nature Med. 8: 1089-1097, 2002. [PubMed: 12219085] [Full Text: https://doi.org/10.1038/nm763]