HGNC Approved Gene Symbol: STAT4
Cytogenetic location: 2q32.2-q32.3 Genomic coordinates (GRCh38): 2:191,029,576-191,151,596 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2-q32.3 | {Systemic lupus erythematosus, susceptibility to, 11} | 612253 | 3 | |
| Disabling pansclerotic morphea of childhood | 620443 | Autosomal dominant | 3 |
STAT4 is phosphorylated in response to interleukin-12 (see IL12B; 161560) and is essential for IL12 signal transduction. For further information on STATs, see STAT1 (600555).
Yamamoto et al. (1997) cloned the human STAT4 cDNA. They suggested that STAT4 and STAT1, which both map to chromosome 2q32, may have arisen via a tandem gene duplication. However, STAT1 was expressed ubiquitously, whereas STAT4 was expressed in specific tissues, including spleen, heart, brain, peripheral blood cells, and testis.
Yamamoto et al. (1997) mapped the STAT4 and STAT1 genes to chromosome 2q32.2-q32.3 by fluorescence in situ hybridization.
Diefenbach et al. (1999) studied the relationship of IL12 and nitric oxide synthase-2 (NOS2; 163730) to innate immunity to the parasite Leishmania in mice. In the absence of NOS2 activity, IL12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer cells for cytotoxicity or interferon-gamma (IFNG; 147570) release, and failed to activate TYK2 (176941) and to tyrosine-phosphorylate STAT4, the central signal transducer of IL12, in NK cells. Activation of TYK2 in NK cells by IFN-alpha/beta (type I interferon; see 147660) also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity in the mouse.
Cell-mediated immunity is dependent on IL12 production by macrophages and dendritic cells, which in turn stimulates IFNG (147570) secretion by natural killer cells and leads to Th1 cell activation. By RNAse protection assays, immunofluorescence microscopy, and Western blot analysis, Frucht et al. (2000) showed that IFNG and lipopolysaccharide (LPS) synergistically induce the expression of STAT4 in purified human monocytes and dendritic cells. The Th2 cytokines IL4 (147780) and IL10 (124092) blocked the induction of STAT4 expression by IFNG and LPS. Although activated monocytes produce IL12, they possess only the beta-1 IL12 receptor (IL12RB1; 601604) and not the beta-2 receptor (IL12RB2; 601642) and therefore do not bind IL12 well. Frucht et al. (2000) noted that IFNA had been shown to induce STAT4 phosphorylation in human lymphoid cells. They showed that, unlike in the mouse, incubation of purified human monocytes with IFNA induced the phosphorylation of STAT4. By immunohistochemistry, Frucht et al. (2000) demonstrated that rheumatoid synovial macrophages express STAT4. The authors concluded that IFNA may complement the action of IL12 signaling when IL12 or its receptor are unavailable.
Lovato et al. (2003) found that intestinal T cells from Crohn disease (see 266600) patients, but not healthy volunteers, showed constitutive activation of STAT3 (102582) and STAT4, suggesting that there is abnormal STAT/SOCS (see SOCS3; 604176) signaling in Crohn disease.
Pang et al. (2007) investigated the expression of IL12B, IFNG, and the activational state of STAT4 signaling in mucosal tissues at the site of disease in 30 Chinese patients with active ulcerative colitis (UC; see 266600) compared with 30 healthy controls. They found increased mRNA expression of IL12B, but not IFNG, in the UC patients, and Western blot analysis demonstrated increased levels of STAT4 in the cytoplasm and phosphorylated STAT4 in the nucleus of mucosal cells from UC patients. The authors concluded that a heightened, perhaps persistent, activational state of IL12/STAT4 and/or IL23/STAT4 signaling may be present in active Chinese UC patients and may be involved in the chronic inflammation of UC.
The N-terminal protein interaction domain (N domain) of STAT4 is required for STAT4 activation after IL12 signaling. Ota et al. (2004) showed that mutations in the N domain of STAT4 block N-domain dimerization and the assembly of nonphosphorylated STAT4 dimers and prevent STAT4 phosphorylation by cytokine receptors. N-domain dimerization was observed for other STAT family members, but was homotypic in character. Ota et al. (2004) proposed that the preassociation of nonphosphorylated STAT dimers may allow the formation of active dimers after activation.
Shin et al. (2005) identified several transcriptional regulatory elements in the STAT4 promoter, but no mutations could be detected in the elements in 91 patients with asthma or arthritis. Instead, STAT4 expression was drastically increased in T cells following treatment with a DNA methyltransferase inhibitor. Truncation of methylation sites in the proximal regulatory elements of the STAT4 promoter markedly enhanced transcriptional activity. Shin et al. (2005) proposed that, in T cells, regulation of STAT4 expression is associated with DNA hypermethylation rather than promoter polymorphisms.
Yap et al. (2005) identified Ikaros (IKZF1; 603023)-binding elements in the 5-prime flanking regions of pufferfish, mouse, and human STAT4. Transactivation, electrophoretic mobility shift, and RNA interference analyses showed that Ikaros bound to the STAT4 promoter and was involved in regulation of STAT4 in human T cells.
Susceptibility to Systemic Lupus Erythematosus
Since linkage peaks containing the STAT4 gene had been reported in genome scans of patients with systemic lupus erythematosus (see SLEB11; 612253), Remmers et al. (2007) included the genotyping of 3 series of patients with SLE and control subjects of European ancestry as part of a large case-control disease-association analysis of a linkage region on chromosome 2q associated with rheumatoid arthritis (180300). They found that a haplotype marked by the STAT4 SNP rs7574865 (600558.0001) was strongly associated with SLE, being present on 31% of chromosomes of case patients and 22% of those of controls (P = 1.87 x 10(-9); odds ratio for having the risk allele in chromosomes of patients vs those of controls, 1.55). Homozygosity for the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for SLE and a 60% increased risk for rheumatoid arthritis. Independently, Gateva et al. (2009) and Han et al. (2009) replicated the association of SLE susceptibility with STAT4 at rs7574865.
By measuring serum IFNA activity and IFNA-induced gene expression in peripheral blood cells (PBMCs) from a cohort of 270 SLE patients of different ethnic backgrounds, Kariuki et al. (2009) showed that the T allele of the STAT4 SNP rs7574865 was simultaneously associated with both lower serum IFNA activity and greater IFNA-induced gene expression. Although the IRF5 (607218) SLE risk genotype was associated with higher serum IFNA activity, the influence of STAT4 was dominant on the sensitivity of PBMCs to serum IFNA. Kariuki et al. (2009) concluded that the risk variant of STAT4 is critical in the dysregulation of the IFNA pathway and SLE susceptibility.
Disabling Pansclerotic Morphea of Childhood
In 4 patients from 3 unrelated families with disabling pansclerotic morphea of childhood (DPMC; 620443), Baghdassarian et al. (2023) identified heterozygosity for missense mutations in the STAT4 gene: A635V (600558.0002) in 2 brothers (family 1), inherited from their mildly affected father; A650D (600558.0003) in a Greek man (family 2) and his moderately affected mother; and a de novo H623Y (600558.0004) substitution in a 17-year-old boy (family 3). Functional analysis demonstrated that the mutations caused a gain-of-function effect, and inhibition of JAK (JAK1; 147795)-STAT signaling with ruxolitinib resulted in improvement in the hyperinflammatory fibroblast phenotype in vitro as well as attenuation of inflammatory markers and clinical symptoms in treated patients.
Associations Pending Confirmation
For discussion of a possible association between variation in the STAT4 gene and rheumatoid arthritis, see RA (180300).
For discussion of a possible association between variation in the STAT4 gene and systemic sclerosis, see 181750.
Since linkage peaks containing the STAT4 gene had been reported in genome scans of patients with systemic lupus erythematosus (see SLEB11; 612253), Remmers et al. (2007) included the genotyping of 3 series of patients with SLE and control subjects of European ancestry as part of a large case-control disease-association analysis of a linkage region on chromosome 2q associated with rheumatoid arthritis (180300). They found that a haplotype marked by the STAT4 SNP rs7574865 was strongly associated with SLE, being present on 31% of chromosomes of case patients and 22% of those of controls (P = 1.87 x 10(-9); odds ratio for having the risk allele in chromosomes of patients vs those of controls, 1.55). Homozygosity for the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for SLE and a 60% increased risk for rheumatoid arthritis. Independently, Gateva et al. (2009) and Han et al. (2009) replicated the association of SLE susceptibility with STAT4 at rs7574865.
To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association with SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This new cohort replicated the association with STAT4 at rs7574865 (combined P value = 1.4 x 10(-41), OR = 1.57, 95% confidence interval of 1.49-1.69).
Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with the STAT4 gene at rs7574865 (combined P value = 5.17 x 10(-42), odds ratio = 1.51, 95% confidence interval 1.43-1.61).
By measuring serum IFNA (147660) activity and IFNA-induced gene expression in PBMCs from a cohort of 270 SLE patients of different ethnic backgrounds, Kariuki et al. (2009) showed that the T allele of the STAT4 SNP rs7574865 was simultaneously associated with both lower serum IFNA activity and greater IFNA-induced gene expression. Although the IRF5 (607218) SLE risk genotype was associated with higher serum IFNA activity, the influence of STAT4 was dominant on the sensitivity of PBMCs to serum IFNA. Kariuki et al. (2009) concluded that the risk variant of STAT4 is critical in the dysregulation of the IFNA pathway and SLE susceptibility.
In 2 brothers (family 1) with disabling pansclerotic morphea of childhood (DPMC; 620443), Baghdassarian et al. (2023) identified heterozygosity for a c.1904C-T transition in the STAT4 gene, resulting in an ala635-to-val (A635V) substitution at a highly conserved residue within the SH2 domain. Their mildly affected father, who had a history of oral ulcerations and less severe skin disease without a formal diagnosis, was also heterozygous for the variant, which was not found in the gnomAD database. Studies in transfected HEK293 cells showed greater luciferase activity with the A635V mutant than wildtype STAT4, consistent with a gain-of-function effect. In transfected UA3 cells, elevated levels of mutant STAT4 persisted longer than wildtype, and there was a greater number and variety of differentially expressed genes with the mutant than with wildtype STAT4. Patient primary skin fibroblasts showed enhanced interleukin-6 (IL6; 147620) secretion, with impaired wound healing, less contractility of the collagen matrix, and reduced matrix secretion. Inhibition of JAK (JAK1; 147795)-STAT signaling with ruxolitinib resulted in improvement in the hyperinflammatory fibroblast phenotype in vitro as well as attenuation of inflammatory markers and clinical symptoms in the 2 brothers. Single-cell RNA sequencing revealed expression patterns that were consistent with an immunodysregulatory phenotype, and were ameliorated through JAK inhibition.
In a German man (family 2) who died at age 31 of infection due to disabling pansclerotic morphea of childhood (DPMC; 620443), Baghdassarian et al. (2023) identified heterozygosity for a c.1949C-A transversion in the STAT4 gene, resulting in an ala650-to-asp (A650D) substitution at a highly conserved residue within the SH2 domain. His mother, who developed swan-neck joint deformities of the hands at age 20 years, was also heterozygous for the variant, which was not found in the gnomAD database. Studies in transfected HEK293 cells showed greater luciferase activity with the A650D mutant than wildtype STAT4, consistent with a gain-of-function effect. In transfected UA3 cells, elevated levels of mutant STAT4 persisted longer than wildtype, and there was a greater number and variety of differentially expressed genes with the mutant than with wildtype STAT4.
In a 17-year-old boy (family 3) with disabling pansclerotic morphea of childhood (DPMC; 620443), Baghdassarian et al. (2023) identified heterozygosity for a de novo c.1867C-T transition in the STAT4 gene, resulting in a his623-to-tyr (H623Y) substitution at a highly conserved residue within the SH2 domain. Studies in transfected HEK293 cells showed greater luciferase activity with the H623Y mutant than wildtype STAT4, consistent with a gain-of-function effect. In transfected UA3 cells, elevated levels of mutant STAT4 persisted longer than wildtype, and there was a greater number and variety of differentially expressed genes with the mutant than with wildtype STAT4.
Baghdassarian, H., Blackstone, S. A., Clay, O. S., Philips, R., Matthiasardottir, B., Nehrebecky, M., Hua, V. K., McVicar, R., Liu, Y., Tucker, S. M., Randazzo, D., Deuitch, N., and 29 others. Variant STAT4 and response to ruxolitinib in an autoinflammatory syndrome. New Eng. J. Med. 388: 2241-2252, 2023. [PubMed: 37256972] [Full Text: https://doi.org/10.1056/NEJMoa2202318]
Diefenbach, A., Schindler, H., Rollinghoff, M., Yokoyama, W. M., Bogdan, C. Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science 284: 951-955, 1999. Note: Erratum: Science 284: 1776 only, 1999. [PubMed: 10320373] [Full Text: https://doi.org/10.1126/science.284.5416.951]
Frucht, D. M., Aringer, M., Galon, J., Danning, C., Brown, M., Fan, S., Centola, M., Wu, C.-Y., Yamada, N., Gabalaway, H. E., O'Shea, J. J. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J. Immun. 164: 4659-4664, 2000. [PubMed: 10779770] [Full Text: https://doi.org/10.4049/jimmunol.164.9.4659]
Gateva, V., Sandling, J. K., Hom, G., Taylor, K. E., Chung, S. A., Sun, X., Ortmann, W., Kosoy, R., Ferreira, R. C., Nordmark, G., Gunnarsson, I., Svenungsson, E., and 24 others. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nature Genet. 41: 1228-1233, 2009. [PubMed: 19838195] [Full Text: https://doi.org/10.1038/ng.468]
Han, J.-W., Zheng, H.-F., Cui, Y., Sun, L.-D., Ye, D.-Q., Hu, Z., Xu, J.-H., Cai, Z.-M., Huang, W., Zhao, G.-P., Xie, H.-F., Fang, H., and 55 others. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature Genet. 41: 1234-1237, 2009. [PubMed: 19838193] [Full Text: https://doi.org/10.1038/ng.472]
Kariuki, S. N., Kirou, K. A., MacDermott, E. J., Barillas-Arias, L., Crow, M. K., Niewold, T. B. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J. Immun. 182: 34-38, 2009. [PubMed: 19109131] [Full Text: https://doi.org/10.4049/jimmunol.182.1.34]
Lovato, P., Brender, C., Agnholt, J., Kelsen, J., Kaltoft, K., Svejgaard, A., Eriksen, K. W., Woetmann, A., Odum, N. Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J. Biol. Chem. 278: 16777-16781, 2003. [PubMed: 12615922] [Full Text: https://doi.org/10.1074/jbc.M207999200]
Ota, N., Brett, T. J., Murphy, T. L., Fremont, D. H., Murphy, K. M. N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation. Nature Immun. 5: 208-215, 2004. [PubMed: 14704793] [Full Text: https://doi.org/10.1038/ni1032]
Pang, Y. H., Zheng, C. Q., Yang, X. Z., Zhang, W. J. Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cell. Immunol. 248: 115-120, 2007. [PubMed: 18048021] [Full Text: https://doi.org/10.1016/j.cellimm.2007.10.003]
Remmers, E. F., Plenge, R. M., Lee, A. T., Graham, R. R., Hom, G., Behrens, T. W., de Bakker, P. I. W., Le, J. M., Lee, H.-S., Batliwalla, F., Li, W., Masters, S. L., and 11 others. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. New Eng. J. Med. 357: 977-986, 2007. [PubMed: 17804842] [Full Text: https://doi.org/10.1056/NEJMoa073003]
Shin, H.-J., Park, H.-Y., Jeong, S.-J., Park, H.-W., Kim, Y.-K., Cho, S.-H., Kim, Y.-Y., Cho, M.-L., Kim, H.-Y., Min, K.-U., Lee, C.-W. STAT4 expression in human T cells is regulated by DNA methylation but not by promoter polymorphism. J. Immun. 175: 7143-7150, 2005. [PubMed: 16301617] [Full Text: https://doi.org/10.4049/jimmunol.175.11.7143]
Yamamoto, K., Kobayashi, H., Arai, A., Miura, O., Hirosawa, S., Miyasaka, N. cDNA cloning, expression and chromosome mapping of the human STAT4 gene: both STAT4 and STAT1 genes are mapped to 2q32.2-q32.3. Cytogenet. Cell Genet. 77: 207-210, 1997. [PubMed: 9284918] [Full Text: https://doi.org/10.1159/000134578]
Yap, W.-H., Yeoh, E., Tay, A., Brenner, S., Venkatesh, B. STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells. FEBS Lett. 579: 4470-4478, 2005. [PubMed: 16081070] [Full Text: https://doi.org/10.1016/j.febslet.2005.07.018]