Alternative titles; symbols
HGNC Approved Gene Symbol: STAT3
SNOMEDCT: 1197362009;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,313,324-42,388,442 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Autoimmune disease, multisystem, infantile-onset, 1 | 615952 | Autosomal dominant | 3 |
| Hyper-IgE syndrome 1, autosomal dominant, with recurrent infections | 147060 | Autosomal dominant | 3 |
The STAT3 gene encodes a transcription factor that plays a critical role in mediating cytokine-induced changes in gene expression. Following activation, members of the STAT family translocate to the nucleus and interact with specific DNA elements (summary by Milner et al., 2015).
Akira et al. (1994) purified acute-phase response factor (APRF), also designated STAT3, and cloned the cDNA. At the amino acid level, APRF exhibited 52.5% overall homology with p91, a component of the interferon (IFN)-stimulated gene factor-3 complexes. Also see STAT1 (600555).
Caldenhoven et al. (1996) reported the cloning of a cDNA encoding a variant of the transcription factor STAT3, designated STAT3-beta, that was isolated by screening an eosinophil cDNA library. Compared to wildtype STAT3, STAT3-beta lacks an internal domain of 50 bp located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes an 80-kD protein.
Using Northern blot analysis, Miyoshi et al. (2001) detected expression of a 5.0-kb mouse Stat3 transcript that was highest in liver and heart, intermediate in lung, spleen, brain, testis, and kidney, and lowest in muscle.
Miyoshi et al. (2001) determined that the mouse Stat3 gene contains 24 exons and spans 30 kb. The translation initiation codon is in exon 2, and the stop codon is in exon 24. The gene has a single promoter.
Choi et al. (1996) used fluorescence in situ hybridization to map the STAT3 gene to chromosome 17q21.
Miyoshi et al. (2001) determined that the mouse Stat3 and Stat5a (601511) genes are located next to each other in a tail-to-tail orientation on chromosome 11, with their polyadenylation sites 3.0 kb apart. The order and orientation of genes at this locus, Ptrf (603198)--Stat3--Stat5a--Stat5b (604260)--Lgp1 (608587)--Hcrt (602358), are identical in the region of syntenic homology on human chromosome 17q21.
Acute-phase response factor is a latent cytoplasmic transcription factor that is rapidly activated in response to interleukin-5 (IL5; 147850), interleukin-6 (IL6; 147620), epidermal growth factor (131530), leukemia inhibitory factor (159540), oncostatin M (165095), interleukin-11 (147681), and ciliary neurotrophic factor (118945). After activation, the 89-kD protein binds to IL6 response elements identified in the promoter regions of various IL6-induced plasma-protein and intermediate-early genes. Lutticken et al. (1994) demonstrated that the above listed cytokines cause tyrosine phosphorylation of the APRF. Protein kinases of the JAK family (e.g., 147795) were also rapidly tyrosine phosphorylated, and both APRF and JAK1 associated with the signal transducer gp130 (IL6ST; 600694). Akira et al. (1994) suggested that APRF may play a major role in the gp130-mediated signaling pathway.
Binding of IL5 to its specific receptor activates JAK2 (147796) which leads to the tyrosine phosphorylation of STAT3 proteins. Caldenhoven et al. (1996) found that STAT3-beta, like STAT3, is phosphorylated on tyrosine and binds to the pIRE from the ICAM1 (147840) promoter after IL5 stimulation. Coexpression of STAT3-beta inhibits the transactivation potential of STAT3. These results suggested that STAT3-beta functions as a negative regulator of transcription.
The leptin receptor (601007) is found in many tissues in several alternatively spliced forms, raising the possibility that leptin (164160) exerts effects on many tissues including the hypothalamus. The leptin receptor is a member of the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, Vaisse et al. (1996) assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor, where they are subsequently phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus, where they bind DNA and activate transcription. The investigators assayed the activation of STAT proteins in response to leptin in a variety of mouse tissues known to express the leptin receptor, Obr. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wildtype mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. The dose-dependent activation of STAT3 by leptin was first observed after 15 minutes and later at 30 minutes. The data indicated to Vaisse et al. (1996) that the hypothalamus is a direct target of leptin action and this activation is critically dependent on the gp130-like leptin receptor isoform missing in db/db mice.
Pfeffer et al. (1997) found that STAT3, a transcription factor for acute phase response genes, acts as an adaptor molecule in signal transduction from the type I interferon receptor. They found that it binds to a conserved sequence in the cytoplasmic tail of the IFNAR1 (107450) chain of the receptor and undergoes interferon-dependent tyrosine phosphorylation. The p85 regulatory subunit of phosphatidylinositol 3-kinase, which activates a series of serine kinases, was found to bind to phosphorylated STAT3 and subsequently to undergo tyrosine phosphorylation. The authors concluded that STAT3 acts as an adaptor to couple another signaling pathway to the interferon receptor.
The cytokines LIF (159540) and BMP2 (112261) signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors.
Foley et al. (2002) demonstrated that synthesis of STAT3-beta by erythroleukemia and primary erythroid progenitor cells treated with IL6 silences gamma-globin expression. They identified the STAT3-like binding sequence in both the A-gamma (142200) and G-gamma (142250) promoters.
Ram et al. (2000) studied the roles of the MAP kinases (see MAPK1, 176948) and STAT3 in transformation of NIH 3T3 cells by Q205L Go-alpha (see 139311). Expression of Q205L Go-alpha in NIH 3T3 cells activated STAT3. Coexpression of dominant-negative STAT3 inhibited Q205L Go-alpha-induced transformation of NIH 3T3 cells and activation of endogenous STAT3. Ram et al. (2000) concluded that STAT3 can function as a downstream effector for Q205L Go-alpha and mediate its biologic effects.
In many human cancers and transformed cell lines, STAT3 is persistently activated, and in cell culture, active STAT3 is either required for transformation, enhances transformation, or blocks apoptosis. Bromberg et al. (1999) reported that substitution of 2 cysteine residues within the C-terminal loop of the SH2 domain of the murine Stat3 gene produced a molecule that dimerized spontaneously, bound to DNA, and activated transcription. In immortalized fibroblasts, this mutant Stat3 molecule caused cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the authors concluded that the activated STAT3 molecule by itself can mediate cellular transformation, and the experiments focused attention on the importance of constitutive STAT3 activation in human tumors.
STAT proteins become phosphorylated on tyrosine and translocate to the nucleus after stimulation of cells with growth factors or cytokines. Simon et al. (2000) showed that the RAC1 guanosine triphosphatase (602048) can bind to and regulate STAT3 activity. Dominant-negative RAC1 inhibited STAT3 activation by growth factors, whereas activated RAC1 stimulated STAT3 phosphorylation on both tyrosine and serine residues. Moreover, activated RAC1 formed a complex with STAT3 in mammalian cells. Yeast 2-hybrid analysis indicated that STAT3 binds directly to active but not inactive RAC1 and that the interaction occurs via the effector domain. Simon et al. (2000) concluded that RAC1 may serve as an alternative mechanism for targeting STAT3 to tyrosine kinase signaling complexes.
Chung et al. (1997) identified PIAS3 (605987) as an inhibitor of STAT3 signaling.
Using transient transfection methods, Scoles et al. (2002) showed that both schwannomin (NF2; 607379) and human growth factor-regulated tyrosine kinase substrate HRS (HGS; 604375) inhibited STAT3 activation, and that schwannomin suppressed STAT3 activation mediated by IGF1 (147440) treatment in a human schwannoma cell line. Schwannomin inhibited STAT3 and STAT5 (601511) phosphorylation in a rat schwannoma cell line. Schwannomin with the pathogenic missense mutation Q538P (607379.0006) failed to bind HRS and did not inhibit STAT5 phosphorylation. The authors hypothesized that schwannomin requires HRS interaction to be fully functionally active and to inhibit STAT activation.
Tyr1138 of the leptin receptor long form (LRb; see 601007) mediates activation of the transcription factor STAT3 during leptin (164160) action. To investigate the contribution of STAT3 signaling to leptin action in vivo, Bates et al. (2003) replaced the gene encoding the leptin receptor (Lepr) in mice with an allele coding for replacement of tyr1138 in LRb with a serine residue that specifically disrupts the LRb-STAT3 signal. Like db/db mice, Lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short, and diabetic, s/s mice are fertile, long, and less hyperglycemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY; 162640) is elevated in db/db mice but not in s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. Bates et al. (2003) concluded that LRb-STAT3 signaling mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth, and glucose homeostasis.
Using wildtype STAT3 and an activation mutant, STAT3(Y705F), Bhattacharya and Schindler (2003) demonstrated the existence of a basal nuclear export pathway independent of tyrosine phosphorylation and, by extension, implied the existence of a basal nuclear import pathway. They identified 3 nuclear export signal (NES) elements, 1 involved in poststimulation export and 2 that regulate basal nuclear export, and concluded that STAT3 nuclear export is dependent on multiple NES elements.
Zhang et al. (2003) stated that phosphorylation of ser727 is required for STAT3 activation by diverse stimuli, including ultraviolet (UV) irradiation. They presented evidence that phosphorylation of ser727 involves a signaling pathway that includes ATM (607585), MAPKs, and RSK2 (300075), as well as other downstream kinases or cofactors. In addition, RSK2-mediated ser727 phosphorylation was required for basal and UV-stimulated STAT3 transcriptional activities.
Lovato et al. (2003) found that STAT3 and STAT4 (600558) were constitutively activated in intestinal T cells from Crohn disease patients (see IBD22, 612380), but not in healthy volunteers. Other STAT proteins were not constitutively activated. The STAT3-regulated protein SOCS3 (604176) was also constitutively expressed in Crohn disease T cells. Lovato et al. (2003) concluded that there is abnormal STAT/SOCS signaling in Crohn disease.
Yuan et al. (2005) showed that in response to cytokine treatment, STAT3 is acetylated on a single lysine residue, lys685. Histone acetyltransferase p300 (602700)-mediated STAT3 acetylation on lys685 was reversible by type I histone deacetylase (see 605314). Using a prostate cancer cell line that lacks STAT3, they established cell lines expressing wildtype STAT3 or a STAT3 mutant containing a lys685-to-arg substitution. Their findings showed that lys685 acetylation was critical for STAT3 to form stable dimers required for cytokine-stimulated DNA binding and transcriptional regulation, to enhance transcription of cell growth-related genes, and to promote cell cycle progression in response to treatment with oncostatin M (165095).
McLoughlin et al. (2005) showed that Il6 -/- mice with Staphylococcus epidermidis-induced peritoneal inflammation exhibited impaired T-cell recruitment with reduced expression of chemokine receptors (e.g., CCR5; 601373) and defective expression of chemokines (e.g., CCL4; 182284). Experiments with knockin mice expressing mutated forms of gp130 (IL6ST; 600694) indicated that Il6-mediated T-cell recruitment required gp130-dependent Stat3 activation.
Kokoeva et al. (2005) demonstrated that centrally administered ciliary neurotrophic factor (CNTF; 118945) induces cell proliferation and feeding centers of the murine hypothalamus. Many of the newborn cells expressed neuronal markers and showed functional phenotypes relevant for energy balance control, including the capacity for leptin-induced phosphorylation of STAT3. Coadministration of the mitotic blocker Ara-C eliminated the proliferation of neural cells and abrogated the long-term, but not the short-term, effect of CNTF on body weight. Kokoeva et al. (2005) concluded that their findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis.
T-cell lymphomas lose expression of SHP1 (PTPN6; 176883) due to DNA methylation of its promoter. Zhang et al. (2005) demonstrated that malignant T cells expressed DNMT1 (126375) and that STAT3 could bind sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241) formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and STAT3 siRNA induced DNA demethylation in malignant T cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3 may transform cells by inducing epigenetic silencing of SHP1 in cooperation with DNMT1 and HDAC1.
Most Toxoplasma gondii isolates in Europe and North America belong to 3 clonal lines, designated types I, II, and III. Using microarray, immunofluorescence, and Western blot analyses, Saeij et al. (2007) found that STAT3 and STAT6 (601512) were activated predominantly in fibroblasts infected with types I and III, rather than type II, T. gondii. They determined that the T. gondii Rop16 protein kinase mediated the strain-specific activation of STAT3 and STAT6. Saeij et al. (2007) noted that their results correlated with previous findings showing that type II T. gondii induces high levels of IL12A (161560) and IL12B (161561) secretion, whereas type I T. gondii induces STAT3 activation and prevents IL12 expression.
Bong et al. (2007) found that vertebrate ephrin B1 (EFNB1; 300035) interacted with Stat3 in a tyrosine phosphorylation-dependent manner, resulting in phosphorylation and enhanced transcriptional activation of Stat3.
Ying et al. (2008) demonstrated that, contrary to long-held belief, extrinsic stimuli are dispensable for the derivation, propagation, and pluripotency of embryonic stem (ES) cells. Self-renewal is enabled by the elimination of differentiation-inducing signaling from mitogen-activated protein kinase (see 176948). Additional inhibition of glycogen synthase kinase-3 (see 606784) consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signaling was confirmed by isolating ES cells genetically devoid of STAT3. Ying et al. (2008) concluded that ES cells have an innate program for self-replication that does not require extrinsic instruction. The authors suggested that this property may account for their latent tumorigenicity.
Bai et al. (2008) investigated the effects of IFNG (147570) on vascular smooth muscle cells (VSMCs) through interactions involving STAT proteins. They found that IFNG stimulation phosphorylated both STAT1 and STAT3 in human VSMCs, but not in mouse VSMCs or human endothelial cells. Activation by IFNG induced STAT3 translocation to the nucleus. Microarray analysis identified signaling candidates that were inducible by IFNG and dependent on STAT3, and RT-PCR and immunoblot analyses verified roles for XAF1 (606717) and NOXA (PMAIP1; 604959). STAT3 activation sensitized VSMCs to apoptosis triggered by both death receptor- and mitochondria-mediated pathways. Knockdown of XAF1 and NOXA expression inhibited priming of VSMCs to apoptotic stimuli by IFNG. Immunodeficient mice with human coronary artery grafts were susceptible to the proapoptotic effects of XAF1 and NOXA induced by IFNG. Bai et al. (2008) concluded that STAT1-independent signaling by IFNG via STAT3 promotes death of VSMCs.
Wegrzyn et al. (2009) provided evidence that Stat3 is present in the mitochondria of mouse cultured cells and primary tissues, including the liver and heart. In Stat3-null cells, the activities of complexes I and II of the electron transport chain were significantly decreased. Wegrzyn et al. (2009) identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the electron transport chain. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the electron transport chain. Wegrzyn et al. (2009) concluded that Stat3 is required for optimal function of the electron transport chain, which may allow it to orchestrate responses to cellular homeostasis.
Gough et al. (2009) reported that malignant transformation by activated Ras (190020.0001) is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, Gough et al. (2009) concluded that, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.
Chaudhry et al. (2009) demonstrated that pathogenic IL17 (603149)-producing T-helper cell (Th17) responses in mice are restrained by CD4+ regulatory cells, or T(regs). This suppression was lost upon T(reg)-specific ablation of Stat3, a transcription factor critical for Th17 differentiation, and resulted in the development of a fatal intestinal inflammation. Chaudhry et al. (2009) concluded that T(regs) adapt to their environment by engaging distinct effector response-specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response.
Carro et al. (2010) used reverse engineering and an unbiased interrogation of a glioma-specific regulatory network to reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors, C/EBP-beta (189965) and STAT3, emerged as synergistic initiators and master regulators of mesenchymal transformation. Ectopic coexpression of C/EBP-beta and STAT3 reprogrammed neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the 2 factors in glioma cells led to collapse of the mesenchymal signature and reduced tumor aggressiveness. In human glioma, expression of C/EBP-beta and STAT3 correlated with mesenchymal differentiation and predicted poor clinical outcome. Carro et al. (2010) concluded that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.
Shui et al. (2012) reported an important role for epithelial HVEM (602746) in innate mucosal defense against pathogenic bacteria. HVEM enhances immune responses by NF-kappa-B (see 164011)-inducing kinase-dependent STAT3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic E. coli infection, Hvem-null mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens, and increased mortality. Shui et al. (2012) identified the immunoglobulin superfamily molecule CD160 (604463), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defense. Shui et al. (2012) concluded that their results pinpointed HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicated that targeting HVEM with agonists could improve host defense.
Amebiasis caused by the enteric protozoan parasite Entamoeba histolytica can manifest as asymptomatic colonization, noninvasive diarrhea, dysentery, and extraintestinal infection, including liver abscess, and results in approximately 100,000 deaths worldwide per year. Using an in vitro model with human cells, Marie et al. (2012) showed that expression of LPR conferred increased resistance to amebic cytotoxicity, including CASP3 (600636) activation. The resistance depended on activation of STAT3, but not SHP2 (PTPN11; 176876) or STAT5. The gln223-to-arg (Q223R; 601007.0001) polymorphism in LPR increased susceptibility to amebic cytotoxicity and decreased leptin-dependent STAT3 activation. The authors found that apoptotic genes, including TRIB1 (609461) and SOCS3, which have opposing roles in apoptosis regulation, were highly enriched in a subset of genes uniquely regulated by STAT3 in response to leptin. Marie et al. (2012) concluded that the LPR-STAT3 signaling pathway restricts amebic pathogenesis and reveals a link between nutrition and susceptibility to infection.
By in vitro analysis, Du et al. (2012) showed that overexpression of MIR337-3p (620408) sensitized human nonsmall cell lung cancer (NSCLC; 211980) cells to paclitaxel, a microtubule-targeting agent of the taxane family, and enhanced paclitaxel-induced G2/M arrest. An MIR337-3p mimic also had a similar effect on paclitaxel response in NSCLC cell lines. In vitro and in vivo approaches identified STAT3 and RAP1A (179520) as direct targets that mediated the effects of MIR337-3p on paclitaxel sensitivity. Further analysis showed that the MIR337-3p mimic also sensitized cells to docetaxel, another member of the taxane family. Correlation analysis in NSCLC cell lines suggested that STAT3 is the major endogenous determinant of intrinsic paclitaxel response. Moreover, high MIR337-3p levels and low STAT3 levels appeared to be correlated with increased overall survival in NSCLC patients.
Using yeast 2-hybrid analysis, Ren et al. (2013) found that mouse Sipar (FAM220A; 616628) interacted with Stat3, and they confirmed the interaction by immunoprecipitation and protein pull-down assays. Stat3 also immunoprecipitated endogenous Sipar from mouse brain. In transfected HEK293 cells, Sipar preferentially associated with phosphorylated Stat3 following Il6-mediated Sipar phosphorylation and nuclear accumulation. Sipar did not interact with a phosphorylation-deficient Stat3 mutant. Overexpression of Sipar induced Stat3 dephosphorylation and downregulation of Stat3-dependent genes. Overexpression of Sipar in B16 mouse melanoma cells, which have persistent Stat3 activation, inhibited tumor formation following injection into nude mice. Sipar did not itself show phosphatase activity, but it appeared to promote Stat3 dephosphorylation.
Ren et al. (2015) found that Sipar interacted directly with Stat3 and the phosphatase TC45 (PTPN2; 176887) and enhanced interaction of phosphorylated Stat3 with TC45 in nuclei of transfected MCF7 cells. Cotransfection of Tc45-competent and Tc45-depleted mouse embryonic fibroblasts revealed that Sipar inhibited Il6-dependent Stat3 transcriptional activity mainly through Tc45.
In mice, Olszak et al. (2014) showed that while bone marrow-derived Cd1d (188410) signals contribute to natural killer T (NKT) cell-mediated intestinal inflammation, engagement of epithelial Cd1d elicits protective effects through the activation of Stat3 and Stat3-dependent transcription of Il10, Hsp110 (610703), and Cd1d itself. All of these epithelial elements are critically involved in controlling CD1D-mediated intestinal inflammation. This was demonstrated by severe NKT cell-mediated colitis upon intestinal epithelial cell-specific deletion of IL10, CD1D, and its critical regulator microsomal triglyceride transfer protein (MTP; 157147), as well as deletion of HSP110 in the radioresistant compartment. Olszak et al. (2014) concluded that these studies uncovered a novel pathway of intestinal epithelial cell-dependent regulation of mucosal homeostasis as well as highlighted a critical role for IL10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Kshirsagar et al. (2014) reported that enhanced STAT3 activity in CD4 (186940)-positive/CD45A (see 151460)-negative/FOXP3 (300292)-negative and FOXP3-low effector T cells from children with lupus nephritis (LN; see 152700) correlated with increased frequency of IL17-producing cells within these T-cell populations. Rapamycin treatment reduced both STAT3 activation and Th17 cell frequency in lupus patients. Th17 cells from children with LN exhibited high AKT (164730) activity and enhanced migratory capacity. Inhibition of AKT in cells from LN patients resulted in reduced Th17-cell migration. Kshirsagar et al. (2014) concluded that the AKT signaling pathway plays a significant role in Th17-cell migratory activity in children with LN. They suggested that inhibition of AKT may result in suppression of chronic inflammation in LN.
By flow cytometric analysis, Zhang et al. (2016) demonstrated that the proportion of mouse B cells expressing Cd5 (153340) relative to those expressing Il6ra (147880) was greatly increased in tumors. Western blot analysis showed that Cd5-positive B cells responded to Il6 in the absence of Il6ra. Binding of Il6 to Cd5 led to Stat3 activation via gp130 and its downstream kinase Jak2. Stat3 upregulated Cd5 expression, forming a feed-forward loop in B cells. In mouse tumor models, Cd5-positive B cells, but not Cd5-negative B cells, promoted tumor growth. CD5-positive B cells also showed activation of STAT3 in multiple types of human tumor tissues. Zhang et al. (2016) concluded that CD5-positive B cells play a critical role in promoting cancer.
Ulaganathan et al. (2015) showed that the substitution of a charged arginine for glycine-388 in the FGFR4 SNP rs351855G-A (G388R; 134935.0001) alters the transmembrane-spanning segment and exposes a membrane-proximal cytoplasmic STAT3-binding site Y(390)-(P)XXQ(393). Ulaganathan et al. (2015) demonstrated that such membrane-proximal STAT3-binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently colocalize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 G385R (mouse homolog of human G388R) knockin mice and transgenic mouse models for breast and lung cancers, the authors validated the enhanced STAT3 signaling induced by the FGFR4 G388R variant in vivo. Ulaganathan et al. (2015) concluded that their findings elucidated the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggested that germline variants of cell surface molecules that recruit STAT3 to the inner cell membrane confer a significant risk for cancer prognosis and disease progression.
Glioblastomas (see 137800) arise from astrocytes and their precursors, neural stem cells, and are frequently associated with activating mutations of EGFR (131550). The most common activating mutation of EGFR in glioblastoma is deletion of exons 2 through 7, which generates a constitutively active EGFR, termed EGFRvIII, that induces phosphorylation of STAT3 to drive tumorigenesis. Using RNA sequencing analysis, Western blot analysis, and deletion and knockdown experiments, Jahani-Asl et al. (2016) found that OSMR (601743) was highly expressed in a STAT3-dependent manner in EGFRvIII-expressing human brain tumor stem cells (BTSCs) and mouse astrocytes compared with controls. Chromatin immunoprecipitation and sequencing showed that STAT3 occupied the promoter of the OSMR gene. There was significant overlap among OSMR-, STAT3-, and EGFRvIII-dependent target genes. Immunohistochemical analysis demonstrated that OSMR and EGFRvIII formed a coreceptor complex at the cell membrane, and gp130 (IL6ST; 600694) and wildtype EGFR were not required for the interaction. OSM (165095) signaling induced phosphorylation and activation of EGFR, leading to EGFR-OSMR interaction. Knockdown of OSMR inhibited proliferation of BTSCs and astrocytes. Furthermore, knockdown of Osmr suppressed tumor growth in SCID mice injected with EgfrvIII-expressing astrocytes or BTSCs. Jahani-Asl et al. (2016) concluded that OSMR is a cell surface receptor that defines a feed-forward mechanism with EGFRvIII and STAT3 in glioblastoma pathogenesis.
Lyons et al. (2017) found that activated STAT3 forms a complex with ERBIN (606944) and SMAD2/SMAD3 to negatively regulate TGF-beta signaling by sequestering SMAD2/SMAD3 in the cytoplasm, thus interrupting their ability to modulate transcription of TGF-beta target genes. Suppression of TGF-beta signaling required pretreatment with IL6 (147620) or IL11 (147681) to activate STAT3, which in turn induced ERBIN expression to form the inhibitory complex. Knockdown of STAT3 or ERBIN abolished the suppressive effect of the complex on TGF-beta signaling.
Using a reporter assay in transfected HEK293T cells, Frey-Jakobs et al. (2018) showed that the nuclear zinc finger transcription factor ZNF341 (618269) activated a synthetic STAT3 promoter. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that ZNF341 bound directly to a specific sequence in the STAT3 promoter through several of its zinc finger domains.
Using ChIP-seq, computational, and pull-down analyses, Beziat et al. (2018) found that ZNF341 bound specifically to a bipartite motif present in the promoters of STAT1 and STAT3. Further analysis showed that the ZNF-like motif and the Sp1-like motif contained within the bipartite ZNF341-binding motif acted in synergy to ensure strong binding of ZNF341 to DNA. Overexpression of ZNF341 in HEK293T cells resulted in induction of STAT1 and STAT3 transcription via binding of ZNF341 to the bipartite motif in the STAT1 and STAT3 promoters.
Using mouse and human cells, Zhang et al. (2020) found that STAT3 was subject to reversible S-palmitoylation on cys108. ZDHHC7 (614604) palmitoylated STAT3 and promoted its membrane recruitment and phosphorylation. APT2 (LYPLA2; 616143) depalmitoylated phosphorylated STAT3 and enabled it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhanced STAT3 activation and promoted Th17 cell differentiation, and perturbation of either palmitoylation or depalmitoylation negatively affected Th17 cell differentiation. The authors noted that overactivation of Th17 cells is associated with several inflammatory diseases, including IBD. In a mouse model, pharmacologic inhibition of Apt2 or knockout of Zdhhc7 relieved the symptoms of IBD.
Hyper-IgE Syndrome 1, Autosomal Dominant, with Recurrent Infections
Minegishi et al. (2007) showed that dominant-negative mutations in the STAT3 gene result in the classic multisystem hyper-IgE syndrome-1 (HIES1; 147060), a disorder of both immunity and connective tissue. They found that 8 of 15 unrelated nonfamilial HIES patients had heterozygous STAT3 mutations (see, e.g., 102582.0001-102582.0003). None of the parents or sibs of the patients had the mutant allele, suggesting that the 5 different mutations, all of which were located in the STAT3 DNA-binding domain, occurred de novo. All 5 mutants were nonfunctional by themselves and showed dominant-negative effects when coexpressed with wildtype STAT3.
Holland et al. (2007) likewise found mutations in STAT3 in hyper-IgE syndrome. They found increased levels of proinflammatory gene transcripts in unstimulated peripheral blood neutrophils and mononuclear cells from patients with HIES as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide had higher tumor necrosis factor-alpha (TNFA; 191160) levels than did identically treated cells from unaffected individuals. In contrast, the cells from patients with HIES generated lower levels of monocyte chemoattractant protein-1 (MCP1; 158105) in response to the presence of interleukin-6, suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. Holland et al. (2007) identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of HIES. Eighteen discrete mutations, 5 of which were hotspots, were predicted to affect directly the DNA-binding and SRC homology-2 (SH2) domains.
By flow cytometric and RT-PCR analyses, Ma et al. (2008) demonstrated that HIES patients with heterozygous mutations in STAT3 failed to generate IL17-secreting Th17 cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcription factor RORGT (602943). Ma et al. (2008) proposed that, because Th17 cells are important in immunity against fungal infections, susceptibility to infections in patients with HIES may be explained by their diminished ability to generate Th17 cells.
By flow cytometric analysis following mitogen activation of IL17-expressing blood T cells from healthy controls or patients with particular genetic traits affecting various cytokine signaling pathways, de Beaucoudrey et al. (2008) found that there was considerable interindividual variability in IL17 expression in controls and most patient groups. However, dominant-negative mutations in STAT3 in HIES patients and, to a lesser extent, null mutations in IL12B or IL12RB1 (601604) in patients with mendelian susceptibility to mycobacterial disease (see 209950) impaired development of IL17-producing T cells.
Using flow cytometric analysis, Siegel et al. (2011) demonstrated a significant reduction in central memory (i.e., expressing CD27, 186711, and CD45RO, 151460) CD4 (186940)-positive and CD8 (see 186910)-positive T cells in autosomal dominant HIES patients that was not due to apoptosis or cell turnover. Stimulation of naive T cells in the presence of IL7 (146660) or IL15 (600554) failed to restore memory cell generation in HIES patients. Impaired differentiation was associated with decreased expression of 2 STAT3-responsive transcription factors, BCL6 (109565) and SOCS3 (604176). Siegel et al. (2011) found that HIES patients had increased risk for reactivation of varicella zoster that was associated with poor CD4-positive T-cell responses. HIES patients also had greater detectable Epstein-Barr virus (EBV) viremia that was associated with compromised T-cell memory to EBV. Siegel et al. (2011) concluded that STAT3 has a specific role in central memory T-cell formation.
Crosby et al. (2012) described a patient with food allergies, a high score for HIES, and eosinophilic esophagitis. They identified a thr389-to-ile (T389I; 102582.0007) mutation in the patient's STAT3 gene.
Berglund et al. (2013) noted that a feature of autosomal dominant HIES due to STAT3 deficiency is impaired humoral immunity following infection and vaccination. Using microarray analysis, they analyzed STAT3-deficient and normal human naive B cells after stimulation with CD40L (TNFSF5; 300386) alone or with IL21 (605384). The authors observed upregulation of IL2RA (147730) and IL10 (124092) production in normal cells, but not STAT3-deficient cells. IL2 enhanced differentiation of plasma cells and Ig secretion from IL21-stimulated naive B cells. Berglund et al. (2013) concluded that IL21, via STAT3, sensitizes B cells to the stimulatory effects of IL2, which may play an active role in IL21-induced B-cell differentiation. They proposed that lack of this secondary effect of IL21 may amplify humoral immunodeficiency in patients with mutations in STAT3, IL2RG (308380), or IL21R (605383) due to impaired IL21 responsiveness.
Lyons et al. (2017) found that dominant-negative STAT3 mutations abolished the suppressive effect of the STAT3/ERBIN/SMAD2/SMAD3 complex on TGF-beta signaling in vitro. Dominant-negative STAT3 mutations reduced ERBIN expression, which was associated with increased nuclear localization of SMAD2/SMAD3. Loss of ERBIN expression or presence of dominant-negative STAT3 variants in patient CD4+ T cells resulted in increased FOXP3 (300292) expression with increased levels of Treg cells that was dose-dependent on TGF-beta levels. SMAD3 activation and STAT3 knockdown also potentiated the transcriptional activity of GATA3 (131320), the canonical Th2 transcription factor, and induced expression of IL4RA (147781). Lymphocytes from patients with dominant-negative STAT3 mutations and from individuals with decreased ERBIN expression had increased IL4RA levels and increased STAT6 phosphorylation and activation in response to IL4 (147780), ultimately promoting B-cell development and activation, class switching to IgE, and differentiation of Th2 cells through increased GATA3 expression. Inhibition of SMAD3, TGFBR1 (190181), or IL4 normalized GATA3 expression in mutant lymphocytes, and the authors suggested that IL4RA blockade would also be effective in reducing TGF-beta signaling. The findings linked increased TGF-beta pathway activation in both ERBIN-deficient and STAT3 mutant lymphocytes, resulting in increased Th2 cytokine expression and elevated IgE, which contribute to immune dysregulation and the atopic/allergic phenotypes.
In 10 patients from 7 unrelated families with HIES1, Asano et al. (2021) identified heterozygous nonsense or frameshift mutations in the STAT3 gene. The patients were ascertained from several large cohorts of patients with immune disorders, and the mutations were found by exome sequencing. Detailed in vitro functional expression studies of 150 STAT3 mutations that had been identified in patients with autosomal dominant HIES1 showed that most of the canonical transcripts (95.3%) of these variants encoded STAT3 proteins with little or no STAT3 activity. Fifteen variants were putative loss-of-function alleles. Many of the variants were found to encode truncated proteins that were expressed, produced neoproteins from translation reinitiation codons, or generated isoforms from alternative transcripts. Functional studies using a luciferase assay indicated that autosomal dominant HEIS1 due to STAT3 deficiency is caused by a dominant-negative effect rather than haploinsufficiency.
In a review of the histories of 158 patients with autosomal dominant HIES1 with dominant-negative STAT3 mutations who were enrolled in a large natural history study, Urban et al. (2022) identified 13 malignancies in 11 patients. Five had STAT3 mutations in the DNA-binding domain and 6 had mutations in the SH2 domain.
Infantile-Onset Multisystem Autoimmune Disease 1
In 5 unrelated patients with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified 4 different de novo heterozygous missense mutations in the STAT3 gene (102582.0008-102582.0011). The mutation in the first patient was found by exome sequencing, and the mutations in the subsequent patients were found by sequencing the coding exons of the STAT3 gene in 24 individuals with early-onset autoimmune disorder. In vitro functional expression studies showed that all the mutations resulted in a gain of function, with increased STAT3-responsive reporter activity and an increase in cytokine-related function compared to wildtype and compared to dominant-negative inactivating mutations associated with HIES. Samples from 2 patients showed increased cytokine-related function, including decreased regulatory T-cell numbers.
In 13 patients from 10 families with ADMIO1, Milner et al. (2015) identified 9 different heterozygous missense mutations in the STAT3 gene (see, e.g., 102582.0008; 102582.0012-102582.0014). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene and affected multiple protein domains. In vitro functional expression studies showed that all the mutant proteins had increased basal transcriptional activity and increased activity in response to cytokines compared to wildtype, consistent with a gain of function. The mutations also caused secondary defects in STAT5 and STAT1 phosphorylation. Patient cells showed increased expression of the downstream target SOCS3 (604176) and diminished numbers of regulatory T cells.
Somatic Mutations in Large Granular Lymphocytic Leukemia
T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias (summary by Koskela et al., 2012). Koskela et al. (2012) used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia and used targeted resequencing in a well-characterized cohort of 76 patients with this disorder. Mutations in STAT3 were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hotspots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology-2 (SH2) domain, which mediates the dimerization and activation of STAT protein. The amino acid changes resulted in a more hydrophobic protein surface and were associated with phosphorylation of STAT3 and its localization in the nucleus. In vitro functional studies showed that the Y640F and D661V mutations increased the transcriptional activity of STAT3. In the affected patients, downstream target genes of the STAT3 pathway (IFNGR2, 147569; BCL2L1, 600039; and JAK2, 147796) were upregulated. Patients with STAT3 mutations presented more often with neutropenia and rheumatoid arthritis than did patients without these mutations.
Associations Pending Confirmation
For discussion of a possible association between variation in the STAT3 gene and Crohn disease, see IBD22 (612380).
For discussion of a possible association between variation in the STAT3 gene and susceptibility to multiple sclerosis, see MS (126200).
Alternative splicing of the STAT3 gene produces 2 isoforms, STAT3-alpha and a dominant-negative variant, STAT3-beta. In STAT3-beta, the 55 C-terminal residues of STAT3-alpha, spanning the intrinsic transactivation domain, are replaced by 7 distinct residues. Yoo et al. (2002) generated Stat3-beta-deficient mice by gene targeting. Despite intact expression and phosphorylation of Stat3-alpha, overall Stat3 activity was impaired in Stat3-beta -/- cells. Global comparison of transcription in Stat3-beta +/+ and Stat3-beta -/- cells revealed stable differences. Stat3-beta-deficient mice exhibited diminished recovery from endotoxic shock and hyperresponsiveness of a subset of endotoxin-inducible genes in liver. The hepatic response to endotoxin in wildtype mice was accompanied by a transient increase in the ratio of Stat3-beta to Stat3-alpha. These findings indicated a critical role for Stat3-beta in the control of systemic inflammation.
Welte et al. (2003) generated a strain of mice with tissue-specific disruption of Stat3 in bone marrow cells during hematopoiesis. The deletion caused death of the mice within 4 to 6 weeks after birth with Crohn disease-like pathogenesis (see 266600) in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of myeloid lineage, both in vivo and in vitro. The authors presented evidence that STAT3 may have an essential regulatory function in the innate immune system. In particular, STAT3 may play a critical role in the control of mucosal immune tolerance. A dramatic expansion of myeloid lineages, causing massive infiltration of the intestine with neutrophils, macrophages, and eosinophils, was thought to be caused by pseudoactivated innate immune responses to bacterial lipopolysaccharide as a result of the STAT3 deletion during hematopoiesis.
In cardiomyocyte-specific Stat3 knockout mice, Jacoby et al. (2003) observed significantly more apoptosis after lipopolysaccharide treatment than in wildtype mice, and Stat3 -/- cardiomyocytes secreted significantly more TNFA (191160) in response to lipopolysaccharide than wildtype. Mice with cardiomyocyte-specific Stat3 deficiency spontaneously developed heart dysfunction with age, and histologic examination of aged mice revealed a dramatic increase in cardiac fibrosis compared to wildtype. Jacoby et al. (2003) concluded that STAT3 is crucial in cardiomyocyte resistance to inflammation and other acute injury and in the pathogenesis of age-related heart failure.
Wang et al. (2004) showed that constitutive activation of Stat3 suppressed tumor expression of proinflammatory mediators in mice. Introducing Stat3-beta, a dominant-negative variant, or Stat3 antisense into mouse tumor cell lines increased expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. Wang et al. (2004) concluded that STAT3 signaling in tumors negatively regulates inflammation, dendritic cell activity, and T-cell immunity. They proposed that selective inhibition of STAT3 signaling would have not only antitumor effects by suppressing growth and inducing apoptosis, but would also activate innate and adaptive antitumor immunity.
Using gene targeting, Maritano et al. (2004) showed that in vivo Stat3-beta is not a dominant-negative factor. In the absence of Stat3-alpha, Stat3-beta rescued the embryonic lethality of the null mutation and could induce expression of specific Stat3 target genes. However, Stat3-alpha was essential for modulating cellular responses to Il6 and mediating Il10 function in macrophages.
Inoue et al. (2004) showed that mice with liver-specific deficiency of STAT3, generated using the Cre-loxP system, showed insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC1A; 604517), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations, and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus (222100, 125853).
Hokuto et al. (2004) showed that cell-selective deletion of Stat3 in mouse respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress, as well as increased epithelial cell injury and inflammatory responses. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B (SFTPB; 178640) improved survival and lung histology in Stat3-deleted mice during hyperoxia. Hokuto et al. (2004) concluded that expression of STAT3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury.
To assess the effect of Stat3 deficiency on mouse skin tumor development, Chan et al. (2004) used the tumor initiator 7,12-dimethylbenz(alpha)anthracene (DMBA) and the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in the 2-stage chemical carcinogenesis model. Stat3-deficient mice showed significantly reduced epidermal proliferation following treatment with TPA because of a defect in progression of the cell cycle from G1 to S phase; treatment with DMBA resulted in a significant increase in the number of apoptotic keratinocyte stem cells. Stat3-deficient mice were completely resistant to skin tumor development when DMBA was used as the initiator and TPA as the promoter. Abrogation of Stat3 function using a decoy oligonucleotide inhibited the growth of initiated keratinocytes possessing an activated Hras gene (190020), both in vitro and in vivo. Injection of Stat3 decoy into skin tumors inhibited their growth. Chan et al. (2004) concluded that STAT3 is required for de novo epithelial carcinogenesis through maintaining the survival of DNA-damaged stem cells and through mediating and maintaining the proliferation necessary for clonal expansion of initiated cells during tumor promotion.
Gorogawa et al. (2004) disrupted Stat3 specifically in insulin (INS; 176730)-producing cells in mice (Stat3-insKO mice). They observed increased appetite and obesity at 8 weeks of age or later in Stat3-insKO mice; the phenotype was not detectable before 6 weeks of age. The mutant mice showed partial leptin resistance. Stat3-insKO mice tested at 5, 11, and 24 weeks of age all showed impaired glucose tolerance, primarily due to insufficient insulin secretion. Expression of mRNA for Glut2 (SLC2A2; 138160), Sur1 (ABCC8; 600509), and Vegfa (192240) was significantly reduced in Stat3-insKO islets. Immunohistochemical analysis demonstrated abnormal pancreatic islet morphology with altered distribution of alpha cells. Gorogawa et al. (2004) concluded that STAT3 has a role in maintaining glucose-mediated early-phase insulin secretion and normal islet cell morphology.
Shen et al. (2005) had previously reported that 75% of C57BL/6 mice lacking Stat3 ser727 phosphorylation showed early mortality and growth retardation. They found that the long-term survivors showed no tissue abnormalities but had increased susceptibility to doxorubicin-induced heart failure. Introduction of this mutant allele into strain-129 mice resulted in greater susceptibility to lipopolysaccharide-induced toxicity. Shen et al. (2005) concluded that there is a continued need for normal STAT3 transcriptional activity to resist different noxious challenges mimicking conditions causing adult disease.
Using immunohistochemical analysis, Sano et al. (2005) demonstrated activated STAT3 in epidermal keratinocytes from human psoriatic lesions (see 177900). Transgenic mice with keratinocytes expressing a constitutively active Stat3 developed skin lesions, either spontaneously or in response to wounding, that closely resembled human psoriatic plaques; in transgenic keratinocytes there was upregulation of several molecules linked to the pathogenesis of psoriasis. The development of psoriatic lesions in the transgenic mice required cooperation between Stat3 activation in keratinocytes and activated T cells, and abrogation of Stat3 function by a decoy oligonucleotide inhibited the onset and reversed established psoriatic lesions.
Using a mouse model of spinal cord injury, Okada et al. (2006) showed that Stat3 is a key regulator of reactive astrocytosis in the repair of injured tissue during the subacute phase (initial 14 days after injury). Selective disruption of the Stat3 gene in mice subjected to spinal cord injury resulted in limited migration of reactive astrocytes, widespread infiltration of inflammatory cells, and neural disruption and demyelination compared to wildtype mice.
The report of Niu et al. (2019) describing regulation of STAT3 by fatty-acid- and ZDHHC19 (618671)-mediated palmitoylation was retracted because of anomalies in several figures showing Western blot results, the original films of which could not be located for further examination.
In 3 presumably unrelated Japanese patients with hyper-IgE syndrome-1 (HIES1; 147060), Minegishi et al. (2007) identified heterozygosity for a 3-bp deletion (1387delGTG) in the STAT3 gene, resulting in deletion of a valine at position 463.
Holland et al. (2007) described the same mutation in a Caucasian patient with sporadic HIES1.
In 2 presumably unrelated Japanese patients with hyper-IgE syndrome-1 (HIES1; 147060), Minegishi et al. (2007) identified heterozygosity for a 1144C-T transition in the STAT3 gene, resulting in an arg382-to-trp (R382W) substitution.
In affected members of 7 families segregating hyper-IgE syndrome, Holland et al. (2007) identified heterozygosity for the R382W mutation in the STAT3 gene. Two of the families were black, 1 Hispanic, and the remainder white.
In 1 of the original patients with 'Job syndrome' reported by Davis et al. (1966), Renner et al. (2007) found the same heterozygous R382W mutation. Her 2 sons and a grandson were also affected. Renner et al. (2007) noted that arg382, which is highly conserved and directly involved in DNA binding, accounted for nearly half of the STAT3 mutations identified by Minegishi et al. (2007) and Holland et al. (2007). Also see 102582.0003.
In a Japanese patient with hyper-IgE syndrome-1 (HIES1; 147060), Minegishi et al. (2007) identified heterozygosity for a 1145G-A transition in the STAT3 gene, resulting in an arg382-to-gln (R382Q) substitution.
In affected members of 4 families segregating hyper-IgE syndrome, Holland et al. (2007) identified heterozygosity for the R382Q mutation in the STAT3 gene. One of the families was black and 3 were white.
In affected members of 2 families, 1 white and 1 Asian, segregating hyper-IgE syndrome-1 (HIES1; 147060), Holland et al. (2007) identified heterozygosity for a 1268G-A transition in the STAT3 gene, resulting in an arg423-to-gln (R423Q) substitution. A parent and daughter were affected in the white family, and parent, son, and daughter in the Asian family.
In a white-Hispanic patient with sporadic hyper-IgE syndrome-1 (HIES1; 147060), Holland et al. (2007) identified heterozygosity for a 1145G-T transversion in the STAT3 gene, resulting in an arg383-to-leu (R383L) substitution.
In affected members of 6 families, all white, with hyper-IgE syndrome-1 (HIES1; 147060), Holland et al. (2007) identified heterozygosity for a 1909G-A transition in the STAT3 gene, resulting in a val637-to-met (V637M) substitution.
Crosby et al. (2012) reported an African-American male with hyper-IgE syndrome-1 (HIES1; 147060) who presented with dysphagia resistant to proton pump inhibitors. He had a normal blood cell count and differential with 12% eosinophils and total IgE of 2728 kU/L. His HIES score was 53. Genotype analysis revealed a mutation in exon 12 of the STAT3 gene that resulted in a thr389-to-ile (T389I) substitution.
In a 6-year-old girl with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified a de novo heterozygous c.2147C-T transition in the STAT3 gene, resulting in a thr716-to-met (T716M) substitution at a highly conserved residue in the transactivation domain. The mutation, which was found by exome sequencing, was not present in the dbSNP (build 131), 1000 Genomes Project, or Exome Variant server databases, or in the unaffected parents.
Milner et al. (2015) identified a heterozygous T716M mutation (c.2147C-T, NM_139276)in the STAT3 gene in 3 patients from 2 unrelated families with ADMIO1. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a 15-year-old girl with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified a de novo heterozygous c.1175A-G transition in the STAT3 gene, resulting in a lys392-to-arg (K392R) substitution at a highly conserved residue in the DNA-binding domain. The mutation was not found in the Exome Variant Server or 1000 Genomes Project databases, or in the unaffected parents.
In 2 unrelated boys with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified a de novo heterozygous c.1938C-G transversion in the STAT3 gene, resulting in an asn646-to-lys (N646K) substitution at a highly conserved residue in the SH2 domain. The mutation was not found in the Exome Variant Server or 1000 Genomes Project databases, or in the unaffected parents.
In a 17-year-old girl with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified a de novo heterozygous c.1974G-C transversion in the STAT3 gene, resulting in a lys658-to-asn (K658N) substitution at a highly conserved residue in the SH2 domain. The mutation was not found in the Exome Variant Server or 1000 Genomes Project databases, or in the unaffected parents.
In a patient with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Milner et al. (2015) identified a de novo heterozygous c.1988C-T transition (c.1988C-T, NM_139276) in the STAT3 gene, resulting in a thr663-to-ile (T663I) substitution in the SH2 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP database.
In a patient with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Milner et al. (2015) identified a de novo heterozygous c.1032G-C transversion (c.1032G-C, NM_139276) in the STAT3 gene, resulting in a gln344-to-his (Q344H) substitution in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP database.
In a father and his 2 children with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Milner et al. (2015) identified a heterozygous c.2107G-A transition (c.2107G-A, NM_139276) in the STAT3 gene, resulting in an ala703-to-thr (A703T) substitution at a conserved residue in the TA domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP database. There was evidence of incomplete penetrance in this family.
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