STAT3
protein-codingsignal transducer and activator of transcription 3, the group of SH2 domain containing
Gene summary
The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~75.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007818
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014414
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014414
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007818
Submitter: ClinGen
*STAT3* was first reported in relation to autosomal dominant hyper IgE syndrome (HIES) in 2007 (PMID: 17881745). *STAT3* loss-of-function (LOF) variants are associated with elevated serum IgE, eczema, and recurrent skin and respiratory tract infections. Patients also have other clinical manifestations that display variable expressivity, including eosinophilia, chronic mucocutaneous candidiasis, systemic allergic manifestations, and extra-hematopoietic features. Over 143 heterozygous variants of *STAT3* had been reported in patients with HIES (PMID: 34137790). These 143 variants include 114 missense mutations, 21 in-frame indels, and 8 nonsense or frameshift indels. Deep intronic variants have also been identified in *STAT3* and have been shown to result in dominant negative (DN) effect on *STAT3* function (PMID: 31346092). Most of the mutations cluster to the DNA binding domain and SH2 domain. For this curation, 14 variants in 14 probands in 4 publications are included (PMID: 17676033, 18602572, 22751495, 31346092). The maximum score for genetic evidence (12 pts.) was reached in this curation and no further variants are included. This gene-disease association is also supported by functional assays, animal models and rescue experiments. After receptor-ligand binding, STAT3 is phosphorylated by receptor associated Janus kinases (JAK), causing formation of STAT homo- or heterodimers, followed by translocation into the nucleus to act as a transcription factor. Mechanistically, STAT3 mutated HIES is driven by dominant negative (DN) variants resulting in reduced STAT3 functionality in cells involved with immunity, osteogenesis, and other biological processes. Using a luciferase based STAT3 transcriptional activity assay, transfection of *STAT3* LOF variants into STAT3 sufficient cells demonstrated almost all variants cause a dominant negative (DN) reduction in STAT3 activity (PMID: 34137790). No cases of *STAT3* LOF variants leading to haploinsufficiency were identified using this experimental approach. HIES patients with *STAT3* LOF variants demonstrate variable levels of pSTAT3 compared to WT, but reproducibly show B cell dysfunction, decreased T helper 17 (Th17) CD4 T cell differentiation and elevated frequencies of IgE+ B cells (PMID: 33045280, 18602572). Two distinct mouse models were curated to supported *STAT3* LOF variants as a mechanism of HIES. These two models demonstrated increased IgE production, increased susceptibility to infection, and decreased TH17 CD4 T cell responses, replicating patient phenotypes (PMID: 31026806, 24632714). Rescue experiments using CRISPR base editing demonstrated increased pSTAT3 levels, STAT3 activity and increased STAT3-dependent cytokine signaling following reversion (PMID: 33876960). In a patient with HIES, HSCT resulted in normalization of TH17 CD4 T cell number, serum IgE levels, STAT3-dependent cytokine signaling and improvement in other HIES associated clinical features (PMID:25962528). In summary, *STAT3* is definitively associated with hyper-IgE syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date, December 16, 2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0014414
Submitter: ClinGen
STAT3 was first reported in relation to early-onset multisystem autoimmune disease in 2014 (PMID: 25038750). STAT3 gain-of-function (GOF) variants are associated with lymphoproliferation, autoimmunity and hypogammaglobulinemia. There is a wide array of clinical symptoms observed and is hypothesized to be due to differences in the variant’s location in functional domains of STAT3 (PMID: 31770611). Some STAT3 GOF mutations exhibit incomplete penetrance in the population, suggesting that STAT3 GOF mutations alone are not enough to cause disease in some cases. Over 49 variants have been reported in the literature (PMID: 34366294). For this curation, 10 variants in 10 probands in 3 publications (PMIDs: 25359994, 25349174, 25038750) are included. The maximum score for genetic evidence (12 pts.) was reached in this curation and no further variants are included. This gene-disease association is also supported by expression studies, functional assays, and animal models. STAT3 is important in cytokine and growth factor signaling. STAT3 is phosphorylated by receptor associated Janus kinases (JAK), causing formation of STAT homo- or heterodimers, followed by translocation into the nucleus to act as a transcription factor. STAT3 is widely expressed and is important for many processes in immunity, cell growth and apoptosis. The exact mechanism leading to STAT3 GOF disease is unknown due to the wide array of functions STAT3 can perform. However, there is evidence STAT3 GOF variants impact immune cell function, leading to autoimmunity. STAT3 GOF variants lead to higher levels of functional STAT3 in patient cells (PMID: 25359994), and lead to increases in negative regulators of cytokine signaling, suggesting over-activity of immune cells (PMID: 25359994). Supporting this finding, groups have shown increased differentiation of T helper 17 cells (TH17) in STAT3 GOF patients (PMID: 26343524), a cell type that is implicated in mediating many autoimmune diseases. Lastly, the generation of a mouse model substituting a STAT3 patient variant led to increased incidence of diabetes mediated by CD8 T cells (PMID: 34115115), as identified in a subset of STAT3 GOF patients. Altogether, published evidence suggests the STAT3 GOF variants are leading to immune cells with increased reactivity and likelihood to cause autoimmunity. However, more mechanistic studies are needed to fully understand the range of clinical symptoms seen in patients. Of note, somatic STAT3 GOF mutations have been identified in cases of large granulocytic leukemia (LGL) (PMIDs: 23207521, 22591296) and likely represent a pathogenic driver of this process. There have been reports of individuals with germline STAT3 GOF developing LGL, though the prevalence of LGL cases caused by germline STAT3 GOF variants is unknown. Future review of this curation will need to assess the relationship between LGL and germline STAT3 GOF variants as more research is performed. In summary, STAT3 is definitively associated with early-onset multisystem autoimmune disease and immune deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. STAT3 related early-onset multisystem autoimmune disease and diabetes: Disease-causing gain of function (GOF) variants in STAT3 were first reported to cause early-onset multiorgan autoimmunity and diabetes in 2014 (PMID:25038750). STAT3 GOF variants have been shown to cause early-onset autoimmunity including diabetes and thyroid disease by affecting the regulation of immune cells and through putative impacts on insulin secretion, pancreatic beta-cell function, and pancreatic development (PMID:20215569,28073828). Diabetes may be the presenting feature of STAT3 related early onset multisystem autoimmune disease, and this typically occurs during early infancy, and is often termed neonatal diabetes. Finding a P/LP STAT3 variant on a sequencing panel in an individual with diabetes should prompt awareness of the possibility of other autoimmune conditions developing. Similarly in individuals discovered to have a P/LP STAT3 variant but who have not been diagnosed with diabetes, glucose monitoring is advised, based on the ~30% prevalence of neonatal diabetes in this disorder. In recent years, exome and targeted next generation sequencing (NGS) technologies have identified various missense variants in the binding domain of the STAT3 protein and linked them to early onset autoimmune disease and diabetes in neonatal patients. A single missense variant, p.(Pro330Ser) was functionally characterized and showed hyperinhibition of the transcription factor ISI-1 in rat cells, leading to decreased insulin gene expression in pancreatic beta cells. These findings provide evidence for a link between early onset diabetes and STAT3 activating variants in pancreatic beta cells (PMID:28073828). Another variant was shown to have increased nuclear localization and increased activation of NEUROG3 leading to primary developmental defects in pancreatic organogenesis (PMID:28402852). This was confirmed using patient derived pluripotent stem cells. It remains unclear to what extent these possible variant effects on beta cell gene expression or development contribute to the development of diabetes in the absence of autoimmunity, or whether diabetes in these individuals results primarily due to autoimmune destruction of beta-cells. Thus, activating germline variants (P/LP) in the DNA binding domain of STAT3 are the cause of monogenic neonatal diabetes associated with beta cell autoimmunity. A knock-in mouse model carrying a single copy of this activating STAT3 variant also exhibited a similar autoimmune diabetes phenotype (PMID:34115115). Autoimmune enteropathy, autoimmune thyroid dysfunction, autoimmune pulmonary disease and autoimmune juvenile-onset arthritis are among the other diseases that have been observed in individuals with activating germline STAT3 variants in addition to autoimmune diabetes. However, patients with inactivating germline STAT3 variants causing hyper-IgE recurrent infection syndrome 1 lack these features (Flanagan et al 2014, PMID:25038750). Hyper-IgE recurrent infection syndrome 1 has been definitively associated with inactivating variants in a separate gene-disease validity curation which does not include diabetes. There has been a report of one patient with a variant (R335W) with features of both activating and inactivating variants (PMID: 35750105); diabetes was not a part of this patient’s phenotype. This classification was originally evaluated and approved by the ClinGen SCID/CID GCEP on January 20, 2022 (SOP Version 8). It was reevaluated on May 17, 2024 (SOP Version 11) by the Monogenic Diabetes GCEP and the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0014414
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007818
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014414
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007818
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007818
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Musculoskeletal; Oncologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Oncologic
Rationale: In Hyper-IgE recurrent infection syndrome, among other manifestations, individuals may suffer recurrent mucocutaneous and pulmonary infections, and antintiinfectious prophylaxis (eg, antibiotics, antifungals, and IgG infusions), as well as early and aggressive treatment of infections may be beneficial; The condition may include vascular anomalies, and awareness may be beneficial in management; Individuals may also have susceptibility to malignancies such as non-Hodgkin lymphoma, and awareness may allow early diagnosis and treatment; In Autoimmune disease, multisystem, infantile onset, individuals have been described with immunodeficiency, and awareness may allow antiinfectious prophylaxis as well as early and aggressive treatment of infections; Awarness of sequelae of autoimmune disease (eg, resulting in hypothyroidism) may allow early management of such manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STAT3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_139276.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 146 | 17 | 169 | ||
| missense | 41 | 67 | 236 | 37 | 5 | 386 |
| nonsense | 1 | 9 | 10 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 13 | 15 | ||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 23 | 29 | ||
| Total | 43 | 74 | 287 | 183 | 22 | 609 |
Highest pathogenic variant AF is 0.0000065765244
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_644805.1 | 23 | MANE Select | |
| Ensembl | ENSP00000264657.4 | 23 | MANE Select | |
| RefSeq | NP_001356441.1 | 23 | Standard | |
| RefSeq | NP_001356442.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| stat3 | Danio rerio | Structure: Muller cell Quality: proliferative abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Non-small cell lung cancer - Homo sapiens (human)
- Adipocytokine signaling pathway - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Insulin resistance - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- temperature homeostasis
- eye photoreceptor cell differentiation
- regulation of transcription, DNA-templated
- regulation of transcription by RNA polymerase II
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II repressing transcription factor binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- cytoplasm
- mitochondrial inner membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264657
- Coding exons
- 23
- Length
- 75245
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125724
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.99 | 131 | 419 | 0.313 | 0.0000248 | 5082 |
| Missense (PolyPhen) | 28 | 152.38 | 0.18375 | 1952 | ||
| Synonymous | 0.239 | 158 | 162 | 0.976 | 0.00000979 | 1430 |
| Loss of Function | 6.43 | 1 | 50.1 | 0.0199 | 0.00000255 | 566 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity). {ECO:0000250|UniProtKB:P42227, ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:12359225, ECO:0000269|PubMed:12873986, ECO:0000269|PubMed:15194700, ECO:0000269|PubMed:17344214, ECO:0000269|PubMed:18242580, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:28065600}.;
- Disease
- DISEASE: Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant (AD-HIES) [MIM:147060]: A rare disorder of immunity and connective tissue characterized by immunodeficiency, chronic eczema, recurrent Staphylococcal infections, increased serum IgE, eosinophilia, distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures. {ECO:0000269|PubMed:17676033, ECO:0000269|PubMed:17881745, ECO:0000269|PubMed:23342295, ECO:0000269|PubMed:26293184}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoimmune disease, multisystem, infantile-onset, 1 (ADMIO1) [MIM:615952]: A disorder characterized by early childhood onset of a spectrum of autoimmune manifestations affecting multiple organs, including insulin-dependent diabetes mellitus and autoimmune enteropathy or celiac disease. Other features include short stature, non-specific dermatitis, hypothyroidism, autoimmune arthritis, and delayed puberty. {ECO:0000269|PubMed:25038750, ECO:0000269|PubMed:28073828}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.981
Intolerance Scores
- LoFtool
- 0.0359
- RVIS EVS
- -0.49
- RVIS percentile EVS
- 22.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |