Alternative titles; symbols
HGNC Approved Gene Symbol: IL6R
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:154,405,343-154,469,450 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | [Interleukin 6, serum level of, QTL] | 614752 | 3 | |
| [Interleukin-6 receptor, soluble, serum level of, QTL] | 614689 | 3 | ||
| Hyper-IgE syndrome 5, autosomal recessive, with recurrent infections | 618944 | Autosomal recessive | 3 |
The IL6R gene encodes the alpha subunit of the IL6 (147620) receptor. This subunit binds IL6 directly. The other subunit, gp130 (IL6ST; 600694), is responsible for intracellular signal transduction through the JAK/STAT pathway (summary by Spencer et al., 2019).
Interleukin-6 (IL6; 147620) is a multifunctional cytokine that is essential to the regulation of the immune response, hematopoiesis, and acute-phase reactions. It exerts its many actions through a heterodimeric receptor consisting of 2 membrane-bound glycoproteins: an 80-kD IL6-binding subunit, IL6R-alpha, and gp130 (IL6ST; 600694), which is responsible for signal transduction and stabilization of the alpha-chain ligand complex. Yamasaki et al. (1988) isolated a cDNA encoding the receptor for interleukin-6. They showed that it codes for a protein consisting of 468 amino acids, including a signal peptide of about 19 amino acids and a domain of about 90 amino acids that is similar to a domain in the immunoglobulin superfamily. The cytoplasmic domain of about 82 amino acids lacks a tyrosine/kinase domain, unlike other growth factor receptors.
Wang et al. (2005) determined that the IL6RA gene comprises 10 exons.
Szpirer et al. (1991) assigned the IL6R gene to human chromosome 1 and rat chromosome 2 by Southern analysis of 2 panels of somatic cell hybrids segregating either human or rat chromosomes. An IL6R-like (IL6RL) locus was also assigned to human chromosome 9. By means of fluorescence in situ hybridization, Kluck et al. (1993) mapped the IL6RA gene to 1q21.
Because circulating levels of IL6 and IL6R are reportedly elevated in patients with hyperparathyroidism (see HRPT1; 145000), Nakchbandi et al. (2002) studied whether measures of this cytokine axis could be helpful in determining the risk for bone loss in hyperparathyroidism. They prospectively followed 23 patients with hyperparathyroidism and found that baseline circulating levels of IL6R correlated significantly with rates of bone loss at the total femur (r = -0.53, P less than 0.01). Furthermore, the combination of a serum IL6R in the upper tertile and IL6 in the upper half of values in the whole group defined a subset of patients with a significantly greater rate of yearly bone loss at the total femur than the remainder of the group (P less than 0.05). They concluded that the combined measurements of serum IL6R and IL6 may be helpful in identifying patients with untreated hyperparathyroidism who are more likely to experience bone loss at the total femur.
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.
By coimmunoprecipitation analysis using 2 differently tagged human IL6R variants expressed in COS-7 cells, Schuster et al. (2003) showed that an IL6R dimer existed in the plasma membrane in the absence of IL6. Ligand binding did not appear to affect IL6R dimerization status. When COS-7 cell lysates expressing only 1 of the IL6R variants were mixed, spontaneous dimerization occurred. Schuster et al. (2003) concluded that IL6R dimerization occurs both on the cell surface and in solution.
Hyper-IgE Syndrome 5, Autosomal Recessive, with Recurrent Infections
In 2 unrelated patients with autosomal recessive hyper-IgE syndrome-5 with recurrent infections (HIES5; 618944), Spencer et al. (2019) identified homozygous mutations in the IL6R gene (147880.0002-147880.0003). The mutations, which were found by whole-genome or whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. One mutation was a frameshift, resulting in a complete loss of function, whereas the other was a missense variant causing normal protein expression, but impaired function. Neither was found in the gnomAD database. Patient T cells showed impaired IL6-mediated phosphorylation of STAT1 (600555) and STAT3 (102582), consistent with a loss of function; these defects could be restored by expression of wildtype IL6R.
Association Studies
Wang et al. (2005) screened the IL6R gene for variation associated with type 2 diabetes (125853) in northern European Caucasian and African American ethnic groups. They identified 11 variants with a minor allele frequency over 5%, including 2 amino acid changes and 4 variants in the 3-prime untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but 2 single-nucleotide polymorphisms (SNPs) in the 3-prime untranslated region showed a trend to an association with type 2 diabetes in all Caucasians, and 3 SNPs showed a trend to an association with type 2 diabetes among the subset of northern European Caucasians. Variant V385I was unique to African Americans and was significantly associated with diabetes and diabetic nephropathy. The authors concluded that IL6R is not likely to explain the linkage to diabetes in the 1q21 region (Elbein et al., 1999), but that their results support a minor role of variants in type 2 diabetes risk and suggest that sequence variants may alter IL6R mRNA levels and possibly levels of soluble IL6R (IL6SR). IL6SR is formed by cleavage of IL6R from the cell membrane (Galicia et al., 2004).
Circulating levels of inflammatory markers can predict cardiovascular disease risk. To identify genes influencing the levels of these markers, Reich et al. (2007) genotyped 1,343 SNPs in 1,184 African Americans from the Health, Aging and Body Composition (Health ABC) Study. Using admixture mapping, they found a significant association of IL6SR (see 614689) with European ancestry on chromosome 1 (lod 4.59), in a region (1q21.3) that includes the IL6R gene. Genotyping 19 SNPs showed that the effect was largely explained by an allele of a nonsynonymous SNP in IL6R, rs8192284 (147880.0001), at 4% frequency in West Africans and at 35% frequency in European Americans, first described as associated with IL6SR in a Japanese cohort (Galicia et al., 2004). Reich et al. (2007) replicated this association (P much less than 1.0 x 10(-12)) and also demonstrated a new association with circulating levels of a different molecule, IL6 (P less than 3.4 x 10(-5)) (see 614752). After replication in 1,674 European Americans from Health ABC, the combined result was even more significant: P much less than 1.0 x 10(-12) for IL6SR, and P less than 2.0 x 10(-9) for IL6. After correction for covariates, there was a 1.09- to 1.13-fold increase in IL6SR levels with 1 copy of the C allele of rs8192284 and a 1.24- to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold increase in IL6 levels with 1 copy of the C allele and a 1.22- to 1.43-fold increase with 2 copies. Surveying cell lines from several different ethnic groups showed no evidence of an association of surface IL6R with rs8192284. This finding supported the hypothesis of Galicia et al. (2004) that the mechanism of action of rs8192284 is to affect cleavage efficiency, because the SNP occurs at the proteolytic cleavage site of IL6R.
Doganci et al. (2005) observed that patients with allergic asthma had increased levels of soluble IL6R (sIL6R) in their airways compared with controls. Blockade of sIl6r in a murine model of late-phase asthma led to suppression of Th2 cells in lungs. In contrast, blockade of membrane-bound Il6r (mIl6r) induced local expansion of Foxp3 (300292)-positive/Cd4 (186940)-positive/Cd25 (IL2RA; 147730)-positive regulatory T cells with increased immunosuppressive capacities. These cells, but not Cd4-positive/Cd25-negative cells, expressed Il6ra and showed Il6-dependent Stat3 (102582) phosphorylation. Cells from anti-Il6r antibody-treated mice adoptively transferred to Rag1 (179615)-deficient mice showed marked immunosuppressive and antiinflammatory functions. Doganci et al. (2005) concluded that IL6 signaling controls the balance between effector cells and regulatory T cells in lungs, with sIL6R regulating Th2 cell functions in CD4-positive/CD25-negative T-effector cells lacking mIL6R, and mIL6R controlling cell fate at the beginning of T-cell differentiation by directing CD4-positive naive cells toward Th2 pathways and inhibiting regulatory T-cell differentiation. They suggested that blockade of IL6 signaling may be a useful approach in the treatment of Th2-dependent inflammatory processes, such as allergic asthma.
McFarland-Mancini et al. (2010) noted that IL6 is essential for timely wound healing. Unexpectedly, they found that Il6r-alpha-deficient mice showed no delay in wound healing, although they shared many inflammatory deficits with Il6-deficient mice. Mice lacking both Il6 and Il6r-alpha, or mice lacking Il6 and treated with antibody to Il6r-alpha, exhibited improved wound healing, in terms of macrophage infiltration, fibrin clearance, and wound contraction, compared with Il6-deficient mice. Il6r-alpha-deficient mice appeared to have aberrant MAP kinase activation, which may have contributed to improved healing.
In a study using admixture mapping to locate regions of the genome associated with acute-phase inflammatory markers and soluble receptors, Reich et al. (2007) identified a missense SNP, rs8192284, that was significantly associated with circulating levels of IL6SR (614689). This SNP, an A-to-C transversion that results in an asp358-to-ala (D358A) amino acid substitution, is present in approximately 35% of Europeans and 4% of West Africans and accounted for the admixture peak within a 40-kb segment on chromosome 1q21.3. Galicia et al. (2004), who had identified the association of rs8192284 with IL6SR in Japanese, noted that this SNP occurs at the proteolytic cleavage site of IL6R and that consequently, variability could affect the level of the circulating soluble receptor. Reich et al. (2007) also identified an association between this SNP and IL6 (147620) levels (614752) in both European Americans and African Americans. After correction for covariates, there was a 1.09- to 1.13-fold increase in IL6SR levels with 1 copy of the C allele of rs8192284 and a 1.24- to 1.43-fold increase with 2 copies, and there was a 1.06- to 1.15-fold increase in IL6 levels with 1 copy of the C allele and a 1.22- to 1.43-fold increase with 2 copies. Surveying cell lines from several different ethnic groups showed no evidence of an association of surface IL6R with rs8192284, supporting the hypothesis of Galicia et al. (2004) that the mechanism of action of rs8192284 is to affect cleavage efficiency.
In a woman (P1), born of unrelated English parents, with autosomal recessive hyper-IgE syndrome-5 with recurrent infections (HIES5; 618944), Spencer et al. (2019) identified a homozygous 1-bp deletion (c.548delG, NM_000565.3) in exon 4 of the IL6R gene, resulting in a frameshift and premature termination (Gly183Glufs7) in the cytokine-binding domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient T cells showed reduced IL6R surface expression and absent IL6 (147620)-mediated phosphorylation of STAT1 (600555) and STAT3 (102582), consistent with a loss of function.
In a 15-year-old boy (P2), born of consanguineous Pakistani parents, with autosomal recessive hyper-IgE syndrome-5 with recurrent infections (HIES5; 618944), Spencer et al. (2019) identified a homozygous c.836T-A transversion (c.836T-A, NM_000565.3) in exon 6 of the IL6R gene, resulting in an ile279-to-asn (I279N) substitution near the domain required for gp130 (600694) binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Another homozygous missense variant (H280P) was found at the adjacent codon, but it was determined not to be pathogenic through functional studies. Patient T cells showed normal IL6R surface expression, but significantly impaired IL6-mediated phosphorylation of STAT1 and STAT3 compared to controls, consistent with a functional defect.
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