STAT1
protein-codingsignal transducer and activator of transcription 1, 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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~112.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013956
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: ClinGen
*STAT1* was first reported to be implicated in Immunodeficiency 31B, viral and mycobacterial infections, autosomal recessive, in 2003 (Dupuis et al., PMID: 12590259). 6 Variants (missence and frameshift) that have been reported in 7 probands in 5 publications are included in this curation (PMIDs: 12590259, 16585605, 20841510, 21772053, 32603902). The mechanism of pathogenicity is reported to be loss of function. Absence or impaired protein expression and the abolition or impaired cellular responses to IFN-γ, IFN-α/β, or IFN-λ, are demonstrated in the patients affected, leading to severe and potentially fatal mycobacterial and viral infections. This gene- disease relationship is also supported by experimental evidence. Enriched STAT1 expression was detected in EBV-transformed B cells (PMID 23715323). Nuclear extracts of HeLaS3 cells treated with IFN-γ and IFN-α showed an increase in nuclear localization of STAT1 (PMID: 16319195). Activation of ISGF3 by IFN-α is shown to be impaired in cells of the patients homozygous with respect to the mutated *STAT1* alleles. No IFN-stimulated response element (ISRE)–binding activity was detected in nuclear extracts from the mutated in response to IFN-α (PMID: 12590259). Electrophoretic mobility shift assay (EMSA) showed no γ-activated sequence (GAS)–binding proteins in response to IFN-γ in STAT1 mutant cell. A similar defect was shown in a patient with complete IFN-γR1 deficiency (PMID: 12590259). In summary, there is definitive evidence supporting the relationship between *STAT1* and immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld overtime.
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013956
Submitter: ClinGen
*STAT1* was first reported in relation to Mendelian Susceptibility to Mycobacterial Disease (MSMD), autosomal dominant, in 2001 (Dupuis et al., PMID: 11452125). STAT1 is primarily activated by IFN in the response of the antimicrobial immune system. IFN-γ stimulation leads to STAT1 phosphorylation, inducing its homodimerization to form γ-activating factor (GAF), which is translocated to the nucleus, and binds to γ-activating sequences to induce transcription of target genes (PMID: 35456913). MSMD is a primary immunodeficiency disease characterized by predisposition to clinical disease caused by weakly virulent mycobacteria such as non-tuberculous mycobacteria, Bacillus Calmette Guerin (BCG) and environmental mycobacteria, caused by a single gene mutation (PMID: 25453225). Genetic etiologies of MSMD are involved in the production or response to interferon-γ (IFN-γ). 6 missense variants that have been reported in 7 probands in 4 publications are included in this curation (PMIDs: 11452125, 16934001, 22573496, 36339330). Functional experiments demonstrated impaired phosphorylation, nuclear accumulation and GAF DNA binding activity of the mutant STAT1. Variants reported showed a dominant-negative effect on the gamma interferon activated sequence (GAS) activation, but not on the interferon-stimulated response element (ISRE) activation (PMID: 22573496). Experimental evidence also supports this gene-disease relationship. Expression of STAT1 is widely enhanced in EBV transformed lymphocytes (PMID: 23715323). Defective GAF response which results in impaired mycobacterial immunity could be demonstrated in a mouse fibroblast cell line. Mutant cells showed defective STAT1 phosphorylation and nuclear accumulation upon stimulation by IFN-γ (PMID: 11452125). In summary, *STAT1* is definitively associated with Mendelian Susciptibility to Mycobacterial Disease (MSMD). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013956
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013956
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013427
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013956
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: ClinGen
Autosomal dominant *STAT1* gain of function mutations were first reported to be associated with autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome in 2011 (PMIDs: 21714643 and 21727188). Among the reported *STAT1*-GOF patients, more than 100 different missense variants were detected; most were in the coiled-coil domain and DNA binding domain. R274Q, A267V, T385M, and R274W are hotspot mutations identified in nearly 40% of all patients with STAT1-GOF (PMIDs: 27114460, 32852681 and 33777053). *STAT1* GOF mutations underlie AD Chronic Mucocutaneous Candidiasis (CMC), as well as a wide range of other clinical features, including a variety of infectious and autoimmune diseases, cerebral aneurysms and cancers (PMID: 27114460). Thyroid dysfunction and autoimmune diabetes are among the most frequent autoimmune manifestations reported, at 22% and 4% respectively. 10 missense variants are included in this curation to reach the maximum score for genetic evidence (PMIDs: 21727188, 23541320, 23534974, 22730530, 28139313). Counting disease segregation in 2 families provided a LOD score of 3 and added 1 point to the genetic evidence (PMID: 21727188). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The reported *STAT1*-GOF mutations are demonstrated to result in gain of STAT1 phosphorylation and gain of function for GAF-dependent cellular responses (PMID: 21727188). Also, Impaired development and function of IL-17 and IL-22- producing T cells ex vivo are detected in patients with AD CMCD having *STAT1* GOF mutations. IFN-γ induced prolonged STAT1 phosphorylation in gain of function mutants and significant diminution of IL-17+FOXP3−CD4+ cells (Th17) were also shown in patients with autoimmune manifestations. Consistent with the phenotype of patients with GOF-*STAT1* mutations, GOF-*Stat1* mice had increased STAT1 protein levels, enhanced pSTAT1 upon IFN-γ stimulation and defective IL-17 production after C. albicans inoculation (PMID: 31867619). In a specific pathogen-free model, *Stat1*T385M/+ mice developed sex-biased autoimmunity and exhibited pronounced dysregulation of basal and cytokine-stimulated *Stat1* activation (PMID: 37275873). Janus kinase inhibitor therapy ruxolitinib was shown to decrease STAT1 phosphorylation in response to stimulation with IFN-β and IFN-γ, reverse dysregulated T helper cell responses and lead to resolution of the chronic mucocutaneous candidiasis and autoimmunity caused by *STAT1*- gain of function mutations (PMID: 28139313). In a multicenter retrospective study (Fischer et al., 2024 PMID: 37935260), JAK inhibitor treatment resulted in partial or complete remission of clinical symptoms in most investigated patients with STAT1-GOF. In summary, there is definitive evidence supporting the relationship between *STAT1* and autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld overtime. **Diabetes Addendum (approved by Monogenic Diabetes GCEP 10/23/2024):** Autosomal dominant *STAT1* GOF variants were first implicated in diabetes in 2013. Three patients with polyendocrinopathy, enteropathy, dermatitis, recurrent mucosal and fungal infections, and autoimmune diabetes were found to have *STAT1* GOF variants. The patients were diagnosed with autoimmune diabetes (two GAD+) between 11 months (presenting with ketoacidosis) and 5 years of age (PMID: 23534974). A subsequent international case series of 274 patients from 167 kindreds with *STAT1* variants revealed 11 (4%) patients with autoimmune diabetes. Within this *STAT1* cohort, aneurysms were more common (27% vs. 5%) in patients with autoimmune diabetes (PMID: 27114460). While diabetes has only been seen in a minority of patients, the prevalence is increased over the general population and cases reported have a young age of onset. Therefore, *STAT1* is appropriate to be included on clinical panels for neonatal diabetes. Individuals found to have a *STAT1* variant causative of diabetes should be monitored for other autoimmune enteropathy and endocrinopathy and susceptibility to chronic infections, and those with non-diabetes presentations should undergo glycemic screening.
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013599
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Individuals with autosomal recessive forms demonstrate susceptibility to severe viral and mycobacterial infections (including lethal infections), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals with heterozygous forms may besusceptible to candiasis, and may be susceptible to neoplasms including carcinoma, as well as autoimmune thyroid disease, and awareness may allow prompt diagnosis and treatment; HSCT has beeen described in some STAT1-related conditions
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STAT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007315.4. 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 | 13 | 164 | 1 | 178 | ||
| missense | 37 | 45 | 195 | 6 | 283 | |
| nonsense | 3 | 3 | 2 | 8 | ||
| start loss | 0 | |||||
| frameshift | 13 | 4 | 1 | 18 | ||
| splice donor/acceptor (+/-2bp) | 2 | 4 | 15 | 21 | ||
| Total | 55 | 56 | 226 | 170 | 1 | 508 |
Highest pathogenic variant AF is 0.00012972482
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009330.1 | 23 | MANE Select | |
| Ensembl | ENSP00000354394.4 | 23 | MANE Select | |
| RefSeq | NP_001371809.1 | 22 | Standard | |
| RefSeq | NP_001371810.1 | 24 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| stat1b | Danio rerio | Structure: nucleate erythrocyte Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
- Inflammatory bowel disease (IBD) - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- negative regulation of endothelial cell proliferation
- positive regulation of mesenchymal cell proliferation
- positive regulation of defense response to virus by host
- negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II core promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- double-stranded DNA binding
- DNA-binding transcription factor activity
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- nucleolus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361099
- Coding exons
- 23
- Length
- 56603
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125748
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.15 | 114 | 406 | 0.281 | 0.0000229 | 5031 |
| Missense (PolyPhen) | 19 | 136.74 | 0.13895 | 1752 | ||
| Synonymous | -0.228 | 156 | 152 | 1.02 | 0.00000926 | 1319 |
| Loss of Function | 5.95 | 4 | 48.9 | 0.0818 | 0.00000230 | 568 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426). ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788). It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. {ECO:0000269|PubMed:12764129, ECO:0000269|PubMed:12855578, ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:9724754}.;
- Disease
- DISEASE: Immunodeficiency 31B (IMD31B) [MIM:613796]: A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness. {ECO:0000269|PubMed:12590259, ECO:0000269|PubMed:20841510, ECO:0000269|PubMed:23709754}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 31A (IMD31A) [MIM:614892]: A form of Mendelian susceptibility to mycobacterial disease, a rare condition caused by impairment of interferon-gamma mediated immunity. It is characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Clinical outcome severity depends on the degree of impairment of interferon-gamma mediated immunity. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. IMD31A has low penetrance, and affected individuals have relatively mild disease and good prognosis. IMD31A confers a predisposition to mycobacterial infections only, with no increased susceptibility to viral infections. {ECO:0000269|PubMed:11452125, ECO:0000269|PubMed:16934001, ECO:0000269|PubMed:22573496}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 31C (IMD31C) [MIM:614162]: A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. {ECO:0000269|PubMed:21714643, ECO:0000269|PubMed:21727188, ECO:0000269|PubMed:23709754, ECO:0000269|PubMed:25288569, ECO:0000269|PubMed:26514428}. Note=The disease is caused by mutations affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643). {ECO:0000269|PubMed:21714643}.;
Recessive Scores
- pRec
- 0.962
Intolerance Scores
- LoFtool
- 0.151
- RVIS EVS
- -0.29
- RVIS percentile EVS
- 33.2
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 |