HGNC Approved Gene Symbol: STAT1
Cytogenetic location: 2q32.2 Genomic coordinates (GRCh38): 2:190,969,149-191,014,171 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2 | Immunodeficiency 31A, mycobacteriosis, autosomal dominant | 614892 | Autosomal dominant | 3 |
| Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive | 613796 | Autosomal recessive | 3 | |
| Immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant | 614162 | Autosomal dominant | 3 |
The JAK (see JAK1; 147795)/STAT pathway is an extensive signaling pathway downstream of cytokine receptors (see IL2RG; 308380). STATs are cytosolic proteins of 750 to 800 amino acids with a common structure consisting of an N-terminal oligomerization domain, which favors formation of STAT dimers, followed by a DNA-binding domain and a C-terminal SRC (190090) homology-2 (SH2) domain, which is involved in association between STATs and receptors. STAT1 is critical in signal transduction from both the type I interferons IFNA (see 147660) and IFNB (see 147640) and the type II interferon IFNG (147570). After IFNG stimulation, STAT1 is phosphorylated and homodimerizes. This phosphorylated STAT1 homodimer forms the gamma-activating factor (GAF), which translocates to the nucleus and upregulates transcription of IFNG-regulated genes. In contrast, IFNA or IFNB stimulation produces several products, including GAF and a heterotrimer formed by STAT1, STAT2 (600556), and p48 (ISGF3G; 147574) that is called interferon-stimulated gamma factor-3 (ISGF3) (review by Rosenzweig and Holland, 2005).
The multiprotein complex ISGF3 (see 147574) binds to a 15-bp element, designated the ISRE (interferon-stimulated response element), that is different from the GAS element. Alpha-interferon stimulates transcription by converting the positive transcriptional regulator ISGF3 from a latent to an active form. Fu et al. (1990) purified ISGF3, separated its component proteins, and determined their peptide sequences. Four proteins of 48 (ISGF3G; 147574), 84, 91, and 113 kD (STAT2) make up the ISGF3 complex. Using these peptide sequences, Schindler et al. (1992) constructed degenerate oligonucleotide probes to screen for cDNA clones. They showed that the 91- and 84-kD components arise from 2 differently processed RNA products derived from 1 gene (STAT1). Comparison of the sequences of the 113-kD and the 91/84-kD proteins revealed that they are encoded by closely related but distinct genes.
Copeland et al. (1995) reported that 7 mouse Stat loci mapped in 3 clusters, with each cluster located on a different mouse autosome, numbers 1, 10, and 11. They interpreted the data as indicating that the family had arisen via a tandem duplication of the ancestral locus, followed by dispersion of the linked loci to different mouse chromosomes. Both Stat1 and Stat4 map to the proximal region of mouse chromosome 1, Stat2 and Stat6 map to the distal region of mouse chromosome 10, and Stat3, Stat5A, and Stat5B map to the distal region of mouse chromosome 11. In the human, Yamamoto et al. (1997) found that both STAT1 and STAT4 map to 2q32.2-q32.3. By FISH and radiation hybrid analysis, Haddad et al. (1998) mapped the STAT1 gene to 2q32.
STAT proteins have the dual function of signal transduction and activation of transcription (Darnell et al., 1994). These proteins are activated by phosphorylation on tyrosine in response to different ligands after which they form homodimers or heterodimers that translocate to the cell nucleus where they either directly bind to DNA or act together with other DNA-binding proteins in multiprotein transcription complexes to direct transcription. The first of these proteins to be described, which they termed STAT1 (for signal transduction and activator of transcription-1), is activated by a number of different ligands, including interferon-alpha (IFNA; 147660), interferon-gamma (IFNG; 147570), EGF (131530), PDGF (see 173430), and IL6 (147620). The same tyrosine residue is activated at least by IFN-alpha, IFN-gamma, and EGF. STAT2 (600556), in contrast, is activated by IFN-alpha but not by IFN-gamma or any of the other ligands mentioned above. STAT3 (102582) is known to be activated by IGF, IL6, LIF, and perhaps other ligands but is not activated by IFN-gamma. STAT4 (600558) is present in high concentration in the testis but has not been found in a phosphorylated form in cells. The STAT proteins differ in the DNA sites to which they bind. STAT1 homodimer binds to IFNG-activating sequence (GAS), which is required for IFNG induction. Variations on this site are also used in response to IL6, PDGF, and other ligands.
Ihle (1995) reviewed the Janus kinases (JAKs; e.g., 147795), which couple ligand binding to tyrosine phosphorylation of signaling proteins recruited by cytokine receptor complexes. The STATs belong to this class of signal transduction proteins. Ihle (1996) reviewed the STATs specifically.
Ihle and Kerr (1995) reviewed the activation cascade involving the STATs, the cytokines, the cytokine receptors (see IL2; 147730), and the Janus kinases.
The N-terminal region is highly homologous among the STAT proteins and surrounds a completely conserved arginine residue. Mowen et al. (2001) demonstrated that methylation of arg31 of STAT1 by protein arginine methyltransferase-1 (PRMT1; 602950) is required for transcription induced by IFN-alpha/IFN-beta (147640). Methylthioadenosine, a methyltransferase inhibitor that accumulates in many transformed cells, inhibits STAT1-mediated IFN responses. This inhibition arises from impaired STAT1-DNA binding due to an increased association of the STAT inhibitor PIAS1 (603566) with phosphorylated STAT1 dimers in the absence of arginine methylation. Thus, arginine methylation of STAT1 is an additional posttranslational modification regulating transcription factor function, and alteration of arginine methylation might be responsible for the lack of interferon responsiveness observed in many malignancies.
Spagnoli et al. (2002) found that Stat1 mediated Igf (see IGF1; 147440)-independent apoptotic effects of Igfbp3 (146732) in rat chondrocytes. Igfbp3 upregulated Stat1 mRNA and protein expression and induced Stat1 phosphorylation and nuclear localization.
Takeda et al. (2003) showed that STAT1 interacted with a conserved cytoplasmic domain tyrosine residue of WSX1 (605350), the IL27 (see 608273) receptor, after the residue was phosphorylated. IL27 stimulation induced phosphorylation of STAT1 and expression of TBET (TBX21; 604895) and IL12RB2 (601642) in wildtype, but not WSX1-deficient, naive CD4 (186940)-positive T cells. Together with IL12 (see IL12B; 161561), IL27 augmented IFNG secretion in wildtype, but not WSX1-deficient, naive CD4-positive T cells. Takeda et al. (2003) concluded that the IL27-WSX1 signaling system acts before the IL12R system in STAT1-mediated TBET induction during the initiation of Th1 differentiation.
Hikasa et al. (2003) found p21 (CDKN1A; 116899) downregulation in conjunction with c-fos (164810) upregulation in the lymphocytes of patients with rheumatoid arthritis. Phosphorylation of STAT1 was also decreased in rheumatoid arthritis lymphocytes. Hikasa et al. (2003) determined that c-fos overexpression led to downregulated phosphorylation and dimerization of STAT1, which in turn downregulated p21 gene expression. They concluded that this regulatory pathway may enhance the proliferation of lymphocytes in rheumatoid arthritis patients.
By fluorescence microscopy and immunoprecipitation analysis, Wesemann et al. (2004) found that Ifng induced an association between the N terminus of Tradd (603500) and Stat1 in both the nucleus and cytoplasm of mouse macrophages. Ifng-induced Stat1 activation was enhanced in cells treated with siRNA to Tradd, suggesting that TRADD is a negative regulator of Ifng-induced Stat1 DNA binding, activation, and function.
IFNG stimulation induces the phosphorylation of STAT1 and promotes the formation of STAT1 homodimers, which recognize GAS. IFNA stimulation results in the phosphorylation of both STAT1 and STAT2, thus producing STAT1 homodimers and STAT1/STAT2 heterodimers, which display different DNA-binding behaviors. Hartman et al. (2005) identified numerous STAT1 and STAT2 gene targets on chromosome 22 following IFN stimulation of HeLa cells. IFNG or IFNA treatment led to a complex pattern of DNA-binding activity. IFNG-induced STAT1 homodimers bound sites not occupied by IFNA-induced STAT1 homodimers and vice versa. Also, IFNA-induced STAT1/STAT2 heterodimers bound sites not occupied by IFNA-induced STAT1 homodimers.
Takeuchi et al. (2003) found that measles virus V protein blocked IFNA/IFNB-induced antiviral signaling by blocking STAT1 and STAT2 phosphorylation. V protein had no effect on degradation of STAT proteins.
Rodriguez et al. (2003) found that Hendra and Nipah virus V proteins coprecipitated with STAT1 and STAT2, but not STAT3. Hendra virus V protein inhibited IFN signaling in transfected human embryonic kidney cells and altered STAT1 localization to a predominantly cytoplasmic distribution. Furthermore, Hendra virus V protein prevented IFN-dependent nuclear redistribution of both STAT1 and STAT2 and caused sequestration of STAT1 and STAT2 into a 500-kD cytoplasmic complex.
Kosaka et al. (2008) used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the IFNG (147570) and STAT1 system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wildtype mice, suggesting that NKT cell IFNG production is indispensable for adhesion formation. This response does not depend on STAT4 (605989), STAT6 (601512), IL12 (161560), IL18 (600953), TNF-alpha (191160), TLR4 (603030), or MYD88 (602170)-mediated signals. Wildtype mice increased the ratio of plasminogen activator inhibitor type 1 (PAI1; 173360) to tPA (173370) after cecal cauterization, whereas Ifng-null or Stat1-null mice did not, suggesting that IFNG has a crucial role in the differential regulation of PAI1 and tPA. Additionally, hepatocyte growth factor (HGF; 142409), a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFNG production, providing a potential new way to prevent postoperative adhesions.
Braumuller et al. (2013) showed that the combined action of the T helper-1-cell cytokines IFNG and tumor necrosis factor (TNF; 191160) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumor immunity from oncogene-induced senescence, Braumuller et al. (2013) used a mouse model in which the Simian virus-40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumors by attenuating p53 (191170)- and Rb (614041)-mediated cell cycle control. When combined, Ifng and Tnf drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream Rb hypophosphorylation at ser795. This cytokine-induced senescence strictly requires Stat1 and Tnfr1 (TNFRSF1A; 191190) signaling in addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells permanently arrest Tag-expressing cancers by inducing Ifng- and Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as IFNG and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
As part of antiviral defense, IFN signaling induces nuclear transport of tyrosine (Y)-phosphorylated STAT1 (PY-STAT1) through KPNA nuclear transporters, including KPNA5 (604545). Filoviruses, such as Ebola virus, antagonize STAT1 signaling to counter IFN antiviral effects. Ebola virus VP24 protein (eVP24) binds KPNA to inhibit PY-STAT1 nuclear transport and IFN action. Xu et al. (2014) described the structure, to a resolution of approximately 3 angstroms, of a complex between the C terminus of KPNA5 and eVP24. They showed that eVP24 interacted, with high affinity, with a nonclassical nuclear localization signal (NLS) binding site within armadillo repeat-10 (ARM10) of KPNA5. ARM10 was necessary for efficient PY-STAT1 transport. Binding of eVP24 to KPNA5 inhibited PY-STAT1 nuclear transport, but it did not affect the transport of classical NLS cargo. Xu et al. (2014) concluded that Ebola virus disables cell-intrinsic antiviral signaling to facilitate virus replication without impacting normal cellular cargo transport.
Li et al. (2017) compared the expression of genes in murine mixed glial cell cultures (MGCs) that lacked Stat1, Stat2, or Irf9 (147574) with wildtype MGCs and found that all 3 genes regulated the constitutive expression of a subset of genes that are involved in antiviral response, proteolysis, and retroviral envelope polyprotein production. The number of ISGs was significantly less in Stat1 and Stat2 knockout MGCs than in Irf9 knockout MGCs, suggesting that regulation of ISGF3 (see 147574)-independent genes in response to IFN-alpha depends mainly on Stat1 and Stat2 signaling and to a lesser extent on Irf9 signaling. Despite functional annotation of ISGs in MGCs indicating the possibility of other signaling molecules in regulating the expression of ISGF3-independent genes, microarray results demonstrated and RNase protection assay confirmed that Stat1, Stat2, and Irf9 were the major signaling factors functionally involved in noncanonical IFN-I signaling, as only a small number of ISGs were induced when cells were deficient in all 3 signaling genes. Investigation of the interferon-regulated gene (IRG) response at different times revealed that IFN-alpha treatment induced similar response in IFN-I-signaling in mutant MGCs compared with wildtype, with prolonged kinetics due to increased time for response. Analyses of RNA from the brains of mice that lacked either Stat1 or Irf9 confirmed that IRGs were regulated by IFN-alpha in vivo.
Using quantitative RT-PCR, Wang et al. (2017) found that ISGs were expressed constitutively under homeostatic conditions in immortalized cell lines, primary intestinal and liver organoids, and liver tissues. Knockdown of STAT1, STAT2, or IRF9 in human liver cells decreased the constitutive expression of ISG, and increased the replication of hepatitis C (HCV) and hepatitis E (HEV) viruses. Furthermore, STAT1, STAT2, and IRF9 were each necessary, but not sufficient, to drive constitutive ISG expression. Overexpression of STAT1, STAT2, and IRF9 in human liver cells revealed that these 3 factors function as the unphosphorylated ISGF3 (U-ISGF3) complex independently of activation by exogenous IFN. Analysis of the U-ISGF complex showed that it consists of IRF9 with unphosphorylated STAT1 and STAT2 in the nucleus. U-ISGF3-induced expression of ISGs was independent of IFN and upstream elements of the IFN signaling pathway.
Crystal Structure
Chen et al. (1998) determined the crystal structure of the DNA complex of a 67-kD core fragment of the STAT1 homodimer, lacking only the N-domain and the C-terminal transcriptional activation domain, at 2.9-angstrom resolution. STAT1 utilizes a DNA-binding domain with an immunoglobulin fold, similar to that of nuclear factor kappa-B and the p53 tumor suppressor protein. The STAT1 dimer forms a contiguous C-shaped clamp around DNA that is stabilized by reciprocal and highly specific interactions between the SH2 domain of one monomer and the C-terminal segment, phosphorylated on tyrosine, of the other. The phosphotyrosine-binding site of the SH2 domain in each monomer is coupled structurally to the DNA-binding domain, suggesting a potential role for the SH2-phosphotyrosine interaction in the stabilization of DNA interacting elements.
Immunodeficiency 31A, Autosomal Dominant
Genetic susceptibility to mycobacterial disease (see 209950) has been linked to recessive mutations in the IFNGR1 (107470), IFNGR2 (147569), IL12B, and IL12RB1 (601604) genes, all of which encode components of type-1 cellular immunity. In cells from a French patient with a history of disseminated bacille Calmette-Guerin (BCG) infection (IMD31A; 614892) who had no mutations in any of these genes, Dupuis et al. (2001) observed severely impaired nuclear protein binding to IFNG-activating sequences (GAS) when the cells were stimulated with IFNG or IFNA. The GAS-binding protein, also called the gamma-activating factor (GAF), consists of STAT1 homodimers. Immunofluorescence microscopy demonstrated defective STAT1 accumulation after IFNG stimulation in the nucleus of the patient's cells compared with controls due to poor phosphorylation at tyr701. Phosphorylation of tyr701 is required for STAT1 dissociation from IFNGR1, homodimerization, and nuclear translocation (see Ramana et al. (2000) for review). Northern blot analysis revealed defective ISGF3G transcription in the patient's cells in response to IFNG, whereas MX1 (147150) induction in response to IFNA was normal. Sequence analysis determined that there was no mutation in the patient's JAK1 gene, but identified a leu706-to-ser mutation (L706S; 600555.0001) in the STAT1 gene in the patient and in her daughter; the mutation was not present in the patient's parents. An unrelated American patient with a history of Mycobacterium avium infection was heterozygous for the same mutation. Stat1-deficient mouse fibroblasts transfected with wildtype STAT1, but not those transfected with L706S STAT1, showed nuclear expression and tyr701 phosphorylation of STAT1 after IFNG stimulation, indicating that L706S is a loss-of-function mutation resulting from tyr701 phosphorylation impairment. Dupuis et al. (2001) noted that only antimycobacterial immunity, not antiviral immunity, was compromised in these patients.
Chapgier et al. (2006) characterized 3 STAT1 alleles, L706S, gln463 to his (Q463H; 600555.0004), and glu320 to gln (E320Q; 600555.0005), from otherwise healthy patients with mycobacterial disease. They showed that the 3 alleles were intrinsically deleterious for both IFNG-induced GAF-mediated immunity and IFNA-induced ISGF3-mediated immunity. Q463H and E320Q affected DNA-binding activity of STAT1, whereas L706S impaired phosphorylation of tyr701. The heterozygous patients had impaired IFNG-mediated immunity that made them susceptible to mycobacterial disease, but they were not particularly susceptible to viral disease, suggesting that the 3 alleles were dominant for IFNG-mediated antimycobacterial immunity and recessive for IFNA-mediated antiviral immunity. Using a series of genetic, immunologic, and biochemical approaches, Chapgier et al. (2006) found that L706S, Q463H, and, to a lesser extent, E320Q impaired GAF activity when in heterozygous state, but they impaired both GAF and ISGF3/ISRE activity only in homozygous state.
In 2 unrelated patients from Japan and Saudi Arabia with autosomal dominant STAT1 deficiency, Tsumura et al. (2012) identified heterozygous missense mutations affecting the SH2 domain of STAT1. One mutation, lys673 to arg (K673R; 600555.0023), was hypomorphic and impaired STAT1 tyrosine phosphorylation. The other mutation, lys637 to glu (K637E; 600555.0024), was null and affected both STAT1 phosphorylation and DNA-binding activity. Both alleles were dominant-negative and impaired STAT1-mediated cellular responses to IFNG and IL27, whereas responses to IFNA and IFN-lambda (see 607403) were preserved at normal levels. Tsumura et al. (2012) concluded that the STAT1 SH2 domain is important for tyrosine phosphorylation and DNA binding, as well as antimycobacterial immunity.
In 2 unrelated Danish men (P7 and P8), with IMD31A manifest as adult-onset herpes simplex encephalitis (HSE) after age 60, Mork et al. (2015) identified a heterozygous missense mutation in the STAT1 gene (V266I; 600555.0028). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB1; 147640), CXCL10 (147310), and TNFA (191160) responses to HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. Patient cells did not have impaired responses to the TLR3 (603029) agonist poly(I;C). The findings suggested that STAT1 variants may contribute to HSE susceptibility in adults.
Immunodeficiency 31B, Autosomal Recessive
Dupuis et al. (2003) studied 2 unrelated infants, P1 and P2, with a clinical syndrome of severe mycobacterial and viral diseases (IMD31B; 613796) not consistent with any known primary immunodeficiency. Infant P1 died of disseminated disease with recurrent encephalitis caused by herpes simplex virus-1; infant P2 died of a viral-like illness, but viral cultures and serologies could not be done. Both children had developed disseminated BCG vaccine infection, which was in remission after antibiotic treatment when symptoms of viral infection appeared. STAT1 was considered a likely candidate gene, given its involvement in both the IFN-gamma and IFN-alpha/beta signaling pathways. Each infant was homozygous for a point mutation in STAT1 (600555.0002; 600555.0003). STAT1 interacts with STAT2 (600556) and p48/IRF9 (147574) to form the transcription factor interferon-stimulated gene factor-3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor, IFNGR1 (107470) or IFNGR2 (147569), are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impaired GAF but not ISGF3 activation had been found in individuals with mycobacterial disease (600555.0001). The infants described by Dupuis et al. (2003) represented the first examples of deleterious mutations in the IFN-alpha/beta signaling pathway. Like individuals with IFN-gamma receptor deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gamma receptor deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the 2 infants. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.
Chapgier et al. (2006) reported a 3-month-old infant of first-cousin Pakistani parents who presented with disseminated BCG infection following BCG vaccination. The patient had a diffuse maculopapular rash, massive hepatosplenomegaly, and respiratory distress. In spite of antimycobacterial and antiinflammatory treatment and eventual bone marrow transplantation, the patient died of multiorgan failure after numerous viral infections, including a fulminant Epstein-Barr virus infection, 3 months after transplantation. The patient's mononuclear cells were unable to produce IL12 or IFNG above background levels after stimulation with BCG, and BCG-induced TNF (191160) production was also suppressed. Western blot analysis showed absent expression of STAT1, but normal expression of STAT3. Chapgier et al. (2006) identified a homozygous 1-bp insertion at nucleotide 1928 (600555.0006) that led to a frameshift and a stop codon at nucleotides 1936 to 1938. EMSA analysis showed lack of GAS- and ISRE-binding protein expression after IFNG and IFNA stimulation. FACS analysis demonstrated lack of HLA class II expression after IFNG stimulation. IFNA was unable to suppress replication of herpes simplex or vesicular stomatitis virus replication in the patient's B-cell lines. Chapgier et al. (2006) concluded that STAT1 is critical to both viral and intracellular bacterial infections.
Kong et al. (2010) reported autosomal recessive partial STAT1 deficiency in 2 consanguineous sibs with mycobacterial and viral diseases. A homozygous lys201-to-asn (K201N; 600555.0007) mutation caused abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing STAT1 protein levels by approximately 70%. The K201N mutant STAT1 protein was not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into GAF, heterotrimerization into ISGF3, binding to DNA elements, and activation of transcription. Activation of GAF and ISGF3 was impaired only at early time points in patient cells, and delayed responses were normal. Kong et al. (2010) concluded that early cellular responses to IFNs are critically dependent on the amount of STAT1 and are essential for control of mycobacterial and viral infections.
Immunodeficiency 31C, Autosomal Dominant
By evaluating 14 patients from 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162), van de Veerdonk et al. (2011) identified 2 heterozygous mutations in exon 10 of the STAT1 gene. Both mutations, arg274 to trp (R274W; 600555.0008) and ala267 to val (A267V; 600555.0009), occurred in the coiled-coil domain of STAT1 and resulted in defective responses in Th1 and Th17 cells, characterized by poor production of IFNG, IL17 (IL17A; 603149), and IL22 (605330). IFNG receptor signaling was preserved in these patients, possibly explaining their normal susceptibility to mycobacteria and viruses.
Liu et al. (2011) identified 12 missense mutations in exons 6 through 10 of the STAT1 gene in 36 patients from 20 kindreds with autosomal dominant chronic mucocutaneous candidiasis. All 12 mutations affected a cluster of residues in a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that at least 11 of the 12 candidiasis-associated STAT1 mutations were gain of function, with enhanced induction of GAS binding in response to IFNG, IFNA, or IL27. Studies with the arg274-to-gln (R274Q; 600555.0010) and asp165-to-gly (D165G; 600555.0014) mutations showed that the gain-of-function mechanism involved increased phosphorylation of tyr701 of STAT1 due to impaired nuclear dephosphorylation. Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A- and IL22-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001). Liu et al. (2011) concluded that patients with familial or sporadic autosomal dominant chronic mucocutaneous candidiasis and mutations affecting the coiled-coil domain of STAT1 produce lower amounts of IL17, which renders them susceptible to extracellular fungal disease.
Soltesz et al. (2013) described the genetic, immunologic, and clinical findings in 9 patients with chronic mucocutaneous candidiasis from the Czech Republic, Hungary, Russia, and Ukraine who ranged in age from 9 to 48 years. Using whole-exome sequencing, they identified heterozygous missense mutations in the STAT1 gene in all 9 patients, including 2 novel mutations affecting the coiled-coil domain, asn179 to lys (N179K; 600555.0020) and gln285 to arg (Q285R; 600555.0021), and a mutation affecting the DNA-binding domain, thr385 to met (T385M; 600555.0022). The N179K and Q285R mutations resulted in STAT1 gain of function for GAF-dependent responses. The T385M mutation in the DNA-binding domain, as well as the frequent R274W mutation in the coiled-coil domain, led to increased STAT1 phosphorylation due to loss of dephosphorylation.
In 5 unrelated patients with disseminated infection with dimorphic fungi, including coccidioidomycosis and histoplasmosis, Sampaio et al. (2013) identified 4 different heterozygous missense mutations in the STAT1 gene (see, e.g., A267V, 600555.0009; T385M, 600555.0022; R274G, 600555.0025). Four of the mutations were demonstrated to occur de novo; parental samples from the fifth patient were not available. Three patients also had candidiasis and 1 had recurrent infections since early childhood. In vitro functional expression studies indicated that the mutations resulted in enhanced IFNG-induced STAT1 phosphorylation and increased DNA binding in B cells compared to wildtype, consistent with a gain of function. However, the initial hyperresponsiveness to IFNG was impaired upon restimulation, suggesting that the IFNG tachyphylaxis may be central to the immunologic defect in this disorder. Knockdown of PIAS1 (603566) resulted in near normalization of STAT1 gene expression after restimulation, and treatment of transfected cells or patient cells with a methyl donor resulted in enhanced methyl-associated STAT1, decreased STAT1/PIAS1 interaction, and decreased IFNG-induced STAT1 phosphorylation, suggesting a potential therapeutic use.
Yamazaki et al. (2014) identified 2 novel gain-of-function STAT1 mutations, lys278 to glu (K278E; 600555.0026) in the coiled-coil domain and gly384 to asp (G384D; 600555.0027) in the DNA-binding domain, in 3 Japanese patients with chronic mucocutaneous candidiasis disease. Ectopic expression of the STAT1 mutants in HeLa cells was associated with increased phosphorylation of both mutant and wildtype STAT1 due to impaired dephosphorylation, indicating that heterodimers of mutant and wildtype STAT1 or homodimers of mutant STAT1 had reduced dephosphorylation function. Anti-CD3D (186790)/anti-CD28 (186760) or Candida stimulation of peripheral blood mononuclear cells and CD4-positive T cells resulted in significantly reduced production of IL17A and IL22, but not IL17F, in 4 patients with STAT1 gain-of-function mutations, including the 3 patients with K278E or G384D mutations and 1 patient with the R274Q mutation. Only anti-IL17F autoantibody was detected in sera from 11 of 17 patients with STAT1 gain-of-function mutations. Yamazaki et al. (2014) concluded that impaired production of IL17A and IL22, but not IL17F, is associated with development of chronic mucocutaneous candidiasis disease.
In a 17-year-old boy with IMD31C, Stellacci et al. (2019) identified a de novo heterozygous missense mutation in the STAT1 gene (S466R; 600555.0030). The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells transfected with the mutation showed lower levels of the mutant protein compared to controls, but the mutant protein had a prolonged half-life and did not undergo accelerated degradation. After interferon treatment, the mutant protein demonstrated increased phosphorylation of tyr701 compared to controls, suggesting a possible positive effect of the mutant protein on downstream signaling through increased expression of interferon type I-stimulated genes. Analysis of patient peripheral blood showed an upregulation of both type I and type II interferon signatures associated with increased mRNA levels of interferon-induced genes; these changes were also observed in transfected HEK293 cells. Based on theses data, Stellacci et al. (2019) suggested that the disorder associated with upregulated STAT1 function (a gain-of-function effect) could be considered an interferonopathy.
In their review, Rosenzweig and Holland (2005) noted that the 2 unrelated kindreds reported by Dupuis et al. (2001) with increased susceptibility to mycobacterial infections (IMD31A; 614892), but not viral infections, had the same heterozygous dominant mutation in STAT1 (600555.0001). The mutation hindered STAT1 phosphorylation, leading to impaired STAT1 dimerization and GAF formation. However, because this dominant mutation did not directly interfere with ISGF3 formation, it selectively impaired IFNG-dependent antimycobacterial activity and spared IFNA/IFNB-dependent antiviral activity. In contrast, the 2 patients reported by Dupuis et al. (2003) carried severe homozygous recessive mutations in STAT1 (600555.0002; 600555.0003), leading to complete STAT1 deficiency (IMD31B; 613796). Both patients developed disseminated BCG disease and died with severe viral infections. In these 2 patients, neither GAF nor ISGF3 could form to due complete lack of STAT1.
Liu et al. (2011) noted that germline mutations in STAT1 underlie susceptibility to 3 different types of infectious disease: mycobacterial diseases, viral diseases, and chronic mucocutaneous candidiasis. Patients with STAT1 mutations and mycobacterial and/or viral disease do not suffer from chronic mucocutaneous candidiasis, and patients with chronic mucocutaneous candidiasis caused by other STAT1 mutations present no mycobacterial or viral diseases. Overall, mutations impairing STAT1 function confer autosomal dominant or autosomal recessive susceptibility to intracellular agents through impairment of IFNA/IFNB immunity (viral diseases) and/or IFNG immunity (mycobacterial diseases). In contrast, gain-of-function STAT1 mutations confer autosomal dominant chronic mucocutaneous candidiasis due to enhanced STAT1-mediated cellular responses to STAT1-dependent repressors and STAT3 (102582)-dependent inducers of IL17 (603149)-producing T cells.
Boisson-Dupuis et al. (2012) reviewed STAT1 germline mutations and the diverse immunologic and infections phenotypes that result from them.
Meraz et al. (1996) reported the generation and characterization of mice deficient in Stat1. Stat1-deficient mice showed no overt development abnormalities but displayed a complete lack of responsiveness to either interferon-alpha or interferon-gamma and were highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice responded normally to several other cytokines that activate Stat1 in vitro. These observations documented that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biologic responses and revealed an unexpected level of physiologic specificity for STAT1 action.
Durbin et al. (1996) likewise found that although the STAT1 transcription factor is activated in response to many cytokines and growth factors, disruption of the Stat1 gene in embryonic stem (ES) cells and in mice when homozygous resulted in unresponsiveness to interferon but retained responsiveness to leukemia inhibitory factor (159540) and remained LIF-dependent for undifferentiated growth. The homozygous animals were born at normal frequencies and displayed no gross developmental defects; however, these animals failed to thrive and were extremely susceptible to viral disease. Cells and tissues from the homozygous deficient mice were unresponsive to IFN, but remained responsive to all other cytokines tested.
Shankaran et al. (2001) found that mice lacking the lymphocyte-specific Rag2 gene (179616), the Ifn receptor signal transcription factor Stat1, Ifngr1, or both Rag2 and Stat1, are significantly more susceptible to chemically induced tumor formation than wildtype mice, suggesting that T, NKT, and/or B cells are essential to suppress development of chemically induced tumors. Spontaneous malignant tumors did not occur in wildtype mice, occurred late in half of mice lacking either Rag2 or Stat1, but occurred early in 82% of mice lacking both genes. Transplanted chemically induced tumors from lymphocyte-deficient mice (Shankaran et al., 2001) or from Ifng-unresponsive mice (Kaplan et al., 1998), but not tumors from immunocompetent hosts, were rejected by wildtype mice, indicating that the tumors from immunodeficient mice are more immunogenic and that lymphocytes and the IFNG/STAT1 signaling pathway collaborate to shape the immunogenic phenotype of tumors that eventually form in immunocompetent hosts. Shankaran et al. (2001) proposed that tumors are imprinted by the immunologic environment in which they form and that 'cancer immunoediting' rather than 'immunosurveillance' best describes the protective and sculpting actions of the immune response on developing tumors.
To establish the role of STAT1 in mediating the biologic responses of IFN-alpha in the central nervous system (CNS), Wang et al. (2002) bred transgenic Stat1-null mice with astrocyte production of IFN-alpha. Surprisingly, the Stat1-deficient mice developed earlier onset and more severe neurologic disease with increased lethality compared with mice not deficient in Stat1. Whereas the brain of 2- to 3-month-old mice with astrocyte production of IFN-alpha showed little, if any, abnormality, the brain from the otherwise identical Stat1-deficient mice had severe neurodegeneration, inflammation, calcification with increased apoptosis, and glial activation. However, the cerebral expression of a number of IFN-regulated Stat1-dependent genes increased in the mice with astrocyte production of IFN-alpha but was reduced markedly in Stat1-null mice. Of many other signaling molecules examined, Stat3 alone was activated significantly in the brain of the Stat1-null mice. Thus, in the absence of Stat1, alternative signaling pathways mediate pathophysiologic actions of interferon-alpha in the living brain, giving rise to severe encephalopathy. STAT1 or a downstream component of the JAK/STAT pathway may protect against such IFN-alpha-mediated injury in the CNS.
Kim et al. (2003) found increased osteoclastogenesis in the bones of Stat1-deficient mice, presumably due to loss of negative regulation of osteoclast differentiation by Ifn-beta. However, they also observed enhanced bone formation and accelerated osteoblast differentiation in Stat1 -/- mice, resulting in increased bone mass. Kim et al. (2003) determined that Stat1 interacts with Runx2 (600211) in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation. The loss of Stat1 in mutant osteoblasts resulted in upregulation of Runx2 DNA-binding activity. Kim et al. (2003) determined that the Stat1-Runx2 interaction does not require phosphorylation of Stat1 on tyr701, which is necessary for Stat1 transcriptional activity, and it does not require Ifn signaling. They concluded that latent STAT1 regulates bone remodeling by attenuating the activity of RUNX2 in the cytoplasm.
Xiao et al. (2004) found that Stat1-deficient mice had significant increases in bone mineral density, bone mineral content, and other parameters of bone growth. Osteoblasts derived from Stat1-null mice had decreased expression of Cdkn1a (116899), a cell cycle inhibitor, and Fgf receptor-3 (FGFR3; 134934), a negative regulator of chondrocyte proliferation. Stat1-null osteoblasts showed increased expression of Fgf18 (603726) in vivo and increased responsiveness to Fgf18 in vitro. Xiao et al. (2004) concluded that STAT1 functions not only to directly regulate the cell cycle but also to modify the repertoire of FGF receptor expression.
Leopold Wager et al. (2014) noted that nonprotective immune responses to the Cryptococcus neoformans fungus are associated with Th2-type cytokine production, alternatively activated macrophages, and failure to clear the fungus, whereas protective immune responses are associated with Th1-type cytokine production and classical macrophage activation. The authors infected Stat1-knockout mice intranasally with different strains of C. neoformans. In contrast with wildtype mice, Stat1-knockout mice had significantly increased pulmonary fungal burden, dissemination to the CNS, and nearly 100% mortality. The infection outcome in Stat1-knockout mice was associated with a shift from Th1 to Th2 cytokines, pronounced lung inflammation, and defective classical macrophage activation. Pulmonary macrophages from Stat1-knockout mice exhibited defects in nitric oxide production and expression of alternatively activated macrophage markers. Leopold Wager et al. (2014) concluded that STAT1 is essential for the classical activation of macrophages that occurs during protective anticryptococcal immune responses.
Dupuis et al. (2001) identified a heterozygous T-to-C substitution at nucleotide 2116 of the STAT1 gene, resulting in a leu706-to-ser (L706S) substitution, in a French woman who had developed disseminated BCG infection (IMD31A; 614892) in childhood and in her daughter, who shared the same defective cellular phenotype. The mutation was not detected in the woman's parents. An unrelated 10-year-old American girl who had Mycobacterium avium infection at age 6 years carried the same mutation. The L706S mutation was not found in a healthy cohort or in other patients with mycobacterial disease.
Infant P1, reported by Dupuis et al. (2003) with complete STAT1 deficiency (IMD31B; 613796), died of disseminated disease with recurrent encephalitis caused by herpes simplex virus-1. She had previously developed disseminated BCG vaccine infection, which was in remission after antibiotic treatment at the time symptoms of viral infection appeared. Dupuis et al. (2003) found that she carried a homozygous 2-nucleotide deletion (of AG) in exon 20 of the STAT1 gene at position 1754, 1755, 1756, or 1757, which they designated 1757-1758delAG. The deletion generated a premature stop codon at position 603 in the protein.
Infant P2 described by Dupuis et al. (2003) with complete STAT1 deficiency (IMD31B; 613796) carried a homozygous nucleotide substitution (T to C) in exon 20 of the STAT1 gene, resulting in substitution of a proline for a leucine at amino acid position 600 (L600P). The infant died of a viral-like illness, but viral cultures and serologies could not be done. The child had developed disseminated BCG vaccine infection, which was in remission after antibiotic treatment when symptoms of viral infection appeared.
Chapgier et al. (2006) reported a German child with mycobacterial disease (IMD31A; 614892) who was heterozygous for a G-to-T transversion at nucleotide 1389 of exon 17 of the STAT1 gene, leading to a gln463-to-his (Q463H) substitution. He developed pulmonary M. avium infection at age 2 years, but was 10 years old and well at the time of study. His parents were unrelated, and his paternal grandfather had received prolonged antibiotic treatment for tuberculosis.
Chapgier et al. (2006) reported a German child of unrelated parents who developed disseminated BCG disease (IMD31A; 614892) in infancy. He was heterozygous for a G-to-C transversion at nucleotide 958 in exon 11 of the STAT1 gene, leading to a glu320-to-gln (E320Q) substitution. Antimycobacterial treatment resulted in recovery and good health at age 8 years at the time of the study. The boy's mother had the same mutation and had developed local BCG disease at age 14 years in response to vaccination. The mother's father, who had the same genotype, had disseminated tuberculosis and, later, lupus vulgaris-like disease, while her grandfather had fatal tuberculosis.
Chapgier et al. (2006) reported a Pakistani child of consanguineous parents who had complete STAT1 deficiency (IMD31B; 613796) with disseminated BCG disease and viral diseases. The patient was homozygous for a 1-bp insertion (A) at nucleotide 1928 of the STAT1 gene, resulting in a frameshift and premature termination of the protein. The patient died at age 11 months.
Kong et al. (2010) reported 2 consanguineous Saudi Arabian sibs who suffered multiple infectious episodes with low virulence mycobacterial pathogens and viruses (IMD31B; 613796). The sibs were homozygous for a 603G-T transversion in a conserved region of exon 8 of the STAT1 gene, resulting in a lys201-to-asn (K201N) substitution in the coiled-coil region of STAT1. The mutation caused abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing STAT1 protein levels by approximately 70%. The K201N mutant STAT1 protein was not intrinsically deleterious in terms of most STAT1 functions. Activation of GAF and ISGF3 was impaired only at early time points in patient cells, and delayed responses were normal. The male proband, who was not BCG vaccinated, developed disseminated M. avium disease at 6 years of age and improved with treatment. At 8 years of age, he developed disseminated varicella, followed by candidiasis. Another bout of M. avium disease in the central nervous system occurred at 9 years of age, leading to seizures and eventual blindness. The patient remained hospitalized at the time of report. His sister was BCG vaccinated at birth and developed disseminated disease. She died at 3 years of age from septic shock. The patients' parents were heterozygous for the K201N mutation, and the patients' 2 healthy sibs each carried at least 1 wildtype allele.
In a Dutch family and a British family with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162), van de Veerdonk et al. (2011) identified a heterozygous C-to-T transition at nucleotide 820 in exon 10 of the STAT1 gene. The mutation resulted in an arg274-to-trp (R274W) substitution in the coiled-coil domain of STAT1 that caused defective responses in Th1 and Th17 cells, characterized by poor production of IFNG (147570), IL17 (IL17A; 603149), and IL22 (605330). In addition to candidiasis, the 67-year-old father of the Dutch family had autoimmune hepatitis, and his 38-year-old daughter had autoimmune hemolytic anemia and antiphospholipid antibodies; his 37-year-old son had candidiasis but no autoimmune phenomena. The father and daughter also suffered from chest infections, and the daughter had pulmonary embolism and Pneumocystis jirovecii pneumonia with symptomatic cytomegalovirus infection. The 40-year-old mother of the British family with candidiasis also had hypothyroidism and suffered from chest infections. Her son and daughter both had candidiasis, and the daughter had hypothyroidism; neither were tested for the R274W mutation.
Liu et al. (2011) identified a heterozygous R274W mutation in 3 patients from an Argentine kindred, a German patient, and a French patient who presented in infancy with autosomal dominant chronic mucocutaneous candidiasis. None showed signs of autoimmunity, but the German patient died at age 54 years from squamous cell carcinoma. The R274W mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that R274W was gain of function, with enhanced induction of GAS binding in response to IFNG, IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A- and IL22-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
In a Dutch family and 2 British families with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162), van de Veerdonk et al. (2011) identified a heterozygous C-to-T transition at nucleotide 800 in exon 10 of the STAT1 gene. The mutation resulted in an ala267-to-val (A267V) substitution in the coiled-coil domain of STAT1 that caused defective responses in Th1 and Th17 cells, characterized by poor production of IFNG (147570), IL17 (IL17A; 603149), and IL22 (605330). In addition to candidiasis, 1 member of the Dutch family, as well as her deceased mother, and 1 member of a British family had esophageal or oral carcinoma. Members of both British families also had hypothyroidism, and 1 British patient suffered from chest infections. No autoimmune disease was observed in these 3 families.
Liu et al. (2011) identified a heterozygous A267V mutation in 2 patients from an Israeli kindred who presented in infancy with autosomal dominant chronic mucocutaneous candidiasis. Neither showed signs of autoimmunity. The A267V mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that A267V was gain of function, with enhanced induction of GAS binding in response to IFNG, IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A- and IL22-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Sampaio et al. (2013) identified a de novo heterozygous A267V mutation in the STAT1 gene in a 9.5-year-old Caucasian girl from Arizona who developed disseminated coccidioidomycosis that eventually involved the central nervous system, resulting in death at age 17. In vitro functional expression studies indicated that the mutation resulted in enhanced IFNG-induced STAT1 phosphorylation and increased DNA binding in B cells compared to wildtype, consistent with a gain of function.
Liu et al. (2011) identified a heterozygous arg274-to-gly (R274Q) mutation in the STAT1 gene in 8 patients from 1 Turkish, 1 Japanese, and 2 French kindreds with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). One of the French patients and one of the Turkish patients also showed signs of thyroid autoimmunity. The R274Q mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that R274Q was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). The gain-of-function mechanism involved increased phosphorylation of tyr701 of STAT1 due to impaired nuclear dephosphorylation. Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
By cloning and transfection experiments, Smeekens et al. (2011) found that the R274Q mutation underlying IMD31C inhibited IL12R (see 601604)/IL23R (607562) signaling, likely due to STAT1 hyperphosphorylation. Inhibition of IL12R/IL23R signaling led to diminished Th1/Th17 responses and increased susceptibility to fungal infections.
Liu et al. (2011) identified a heterozygous lys286-to-ile (K286I) mutation in the STAT1 gene in 2 patients from a French kindred who presented at ages 3 years and 5 years with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). Neither showed signs of autoimmunity. The K286I mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that K286I was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous met202-to-val (M202V) mutation in the STAT1 gene in 3 patients from 2 French kindreds who presented as children with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). One patient showed signs of thyroid autoimmunity, and another patient's father, who was of unknown genotype, had candidiasis and died of squamous cell carcinoma at age 55 years. The M202V mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that M202V was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous cys174-to-arg (C174R) mutation in the STAT1 gene in 6 patients from a German kindred who presented as children with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). Three of these patients showed signs of thyroid autoimmunity. Another member of the kindred, who had candidiasis but was of unknown genotype, died at age 54 years of squamous cell carcinoma. The C174R mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that C174R was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous asp165-to-gly (D165G) mutation in a Ukrainian patient who presented as an infant with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). He showed no signs of autoimmunity. The D165G mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that D165G was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). The gain-of-function mechanism involved increased phosphorylation of tyr701 of STAT1 due to impaired nuclear dephosphorylation. Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous thr288-to-ala (T288A) mutation in a patient from a Mexican kindred and 2 patients from a Swiss kindred who presented as infants with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). None of the patients showed signs of autoimmunity. The T288A mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that T288A was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous tyr170-to-asn (Y170N) mutation in a Swiss patient who presented as an infant with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). He also showed signs of thyroid autoimmunity. The Y170N mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that Y170N was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous asp165-to-his (D165H) mutation in a German patient who presented as an infant with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). She also showed signs of thyroid autoimmunity. The D165H mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that D165H was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous met202-to-ile (M202I) mutation in a German patient and 2 patients from a French kindred who presented as children with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). The German child showed no signs of autoimmunity, but one of the French patients developed systemic lupus erythematosus (SLE; 152700). The M202I mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that M202I was gain of function, with enhanced induction of GAS binding in response to IFNG (147570), IFNA (147660), or IL27 (608273). Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A (603149)- and IL22 (605330)-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001).
Liu et al. (2011) identified a heterozygous gln271-to-pro (Q271P) mutation in a German patient who presented at 1 year of age with autosomal dominant chronic mucocutaneous candidiasis (IMD31C; 614162). She showed signs of thyroid autoimmunity and died at age 41 years from squamous cell carcinoma. The Q271P mutation occurred within a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation.
In a 9-year-old Czech girl with IMD31C (614162), Soltesz et al. (2013) identified a c.537C-A transversion in exon 7 of the STAT1 gene. The mutation resulted in an asn179-to-lys (N179K) substitution in the coiled-coil domain of STAT1 that caused a gain of function for GAF-dependent cellular responses. The girl had first experienced oral candidiasis at age 6 months and subsequently developed chronic mucocutaneous candidiasis, and she had low or undetectable IgG2 and IgG4. She had 2 young, healthy sibs and no family history of chronic mucocutaneous candidiasis or immunopathologic disease. The patient died at age 9 years from multiple intracranial aneurysms and intracranial bleeding.
In a 9-year-old Russian girl with IMD31C (614162), Soltesz et al. (2013) identified a c.854A-G transition in exon 10 of the STAT1 gene. The mutation resulted in a gln285-to-arg (Q285R) substitution in the coiled-coil domain of STAT1 that caused a gain of function for GAF-dependent cellular responses. The girl had suffered from chronic mucocutaneous candidiasis since infancy, and she did not respond to her mother's treatments. Oral antifungal medication attenuated chronic mucocutaneous candidiasis exacerbation on several occasions. The first 3 of her mother's pregnancies were terminated, while an older sib was born with a congenital malformation and subsequently died of an undefined chronic illness.
In a 13-year-old Ukrainian boy with IMD31C (614162), Soltesz et al. (2013) identified a c.1154C-T transition in exon 14 of the STAT1 gene. The mutation resulted in a thr385-to-met (T385M) substitution in the DNA-binding domain of STAT1 that caused a gain of STAT1 phosphorylation due to loss of dephosphorylation. The boy had exhibited severe chronic mucocutaneous candidiasis with oral obstruction and dysphagia from infancy. His symptoms were usually controlled by oral antifungal medication, and manifestations in the fingernails subsided after age 10 years. The boy's 9-year-old sister and mother were healthy.
Uzel et al. (2013) identified a heterozygous T385M mutation in 2 unrelated children with IMD31C (614162). One patient presented in infancy with mucocutaneous candidiasis, and the other presented in early childhood with dermatitis, recurrent infections, and enteropathy, but only had 1 episode of mild candidiasis. In vitro functional expression studies showed that the mutation resulted in increased STAT1 phosphorylation, activation, and increased DNA binding in response to IFNG stimulation, consistent with a gain of function. Transfected cells also showed decreased STAT1 dephosphorylation compared to wildtype, indicating prolonged activation. Flow cytometric analysis of patient lymphocytes confirmed increased IFNG-induced STAT1 hyperphosphorylation.
Sampaio et al. (2013) identified a de novo heterozygous T385M mutation in the STAT1 gene in a 21-year-old Caucasian man with a lifetime history of recurrent infections and bone fractures in childhood. He developed mucocutaneous candidiasis at age 7 days, a mycobacterial infection at age 4, and severe disseminated histoplasmosis at age 12. In vitro functional expression studies indicated that the mutation resulted in enhanced IFNG-induced STAT1 phosphorylation and increased DNA binding in B cells compared to wildtype, consistent with a gain of function.
In a Japanese boy with autosomal dominant susceptibility to mycobacterial disease (IMD31A; 614892), Tsumura et al. (2012) identified a heterozygous c.2018A-G transition in exon 22 of the STAT1 gene, resulting in a lys673-to-arg (K673R) substitution in the SH2 domain. The boy had a history of lymph node enlargement at age 3 months after BCG vaccination that was effectively treated with local antiinfective agents. At age 6 years, he developed multifocal osteomyelitis histologically resembling tuberculoid granulomas on the left humerus, 3 vertebrae, and pelvis. PCR failed to detect pathogenic bacteria. Responses to vaccination against viruses were normal. His parents were nonconsanguineous and lacked clinical signs of immunodeficiency, but his older sister had a history of lymph node enlargement after BCG vaccination in infancy that cured spontaneously. The heterozygous K673R mutation was present in the sister and father, but not the mother. Production of TNF (191160) by peripheral blood mononuclear cells was impaired in response to stimulation with lipopolysaccharide and IFNG (147570) in the patient, his father, and his sister, but not his mother. The hypomorphic K673R mutation impaired STAT1 tyr phosphorylation. Confocal microscopy demonstrated that the K673R mutation caused incomplete STAT1 translocation to the nucleus after IFNG stimulation.
In a Saudi Arabian girl with autosomal dominant susceptibility to mycobacterial disease (IMD31A; 614892), Tsumura et al. (2012) identified a heterozygous c.1909A-G transition in exon 22 of the STAT1 gene, resulting in a lys637-to-glu (K637E) substitution in the SH2 domain. The patient developed disseminated BCG disease at age 5 months and presented skin erosion near the BCG vaccination site and on her back. Skin biopsy showed noncaseating granulomatous dermatitis. The patient developed osteomyelitis in her right fibula and zygomatic bone. Mycobacteria from the M. tuberculosis complex were isolated by culture of a fibula biopsy. She was successfully treated with antimycobacterial agents, including isoniazid, rifampin, and ciprofloxacin. Her consanguineous parents lacked clinical signs of immunodeficiency, but they could not be tested for the mutation. Compared to local controls, the patient had partial impairment of IL12B (161561) production after stimulation of whole blood with BCG plus IFNG (147570). The null K637E mutation impaired both STAT1 tyr phosphorylation and DNA-binding activity. Confocal microscopy demonstrated that the K637E mutation caused incomplete STAT1 translocation to the nucleus after IFNG stimulation.
In a patient with IMD31C (614162), manifest as disseminated histoplasmosis, Sampaio et al. (2013) identified a heterozygous c.820C-G transversion in the STAT1 gene, resulting in an arg274-to-gly (R274G) substitution. The mutation was not found in the dbSNP or 1000 Genomes Project databases; parental DNA was not available for segregation analysis. The patient had oral candidiasis at age 16, disseminated histoplasmosis at age 17, and progressive multifocal leukoencephalopathy associated with JC virus at age 31; he died of Pseudomonas-induced sepsis. Arg274 is also mutated in other cases of IMD31C (R274W, 600555.0008 and R274Q, 600555.0010).
In a 20-year-old Japanese woman with IMD31C (614162), Yamazaki et al. (2014) identified heterozygosity for a c.832A-G transition in the STAT1 gene, resulting in a lys278-to-glu (K278E) substitution in the coiled-coil domain. The patient's parents were nonconsanguineous and healthy and carried the wildtype STAT1 sequence. She had recurrent oral thrush since the age of 1 year, recurrent herpes zoster more than 5 times since the age of 4 years, and recurrent stomatitis about once every 2 months. Candida esophagitis developed at age 18 years, and impetigo contagiosa on the right thigh developed at age 19 years. Ectopic expression of the STAT1 K278E mutant in HeLa cells demonstrated that K78E was associated with gain of function due to impaired STAT1 dephosphorylation. Anti-CD3D (186790)/anti-CD28 (186760) or Candida stimulation of peripheral blood mononuclear cells and CD4 (186940)-positive T cells from the patient resulted in significantly reduced production of IL17A (603149) and IL22 (605330), but not IL17F (606496).
In a 35-year-old Japanese woman and her 5-year-old son, both of whom had IMD31C (614162), Yamazaki et al. (2014) identified heterozygosity for a c.1150G-A transition in the STAT1 gene, resulting in a gly384-to-asp (G384D) substitution in the DNA-binding domain. The woman had suffered from repetitive oral thrush and stomatitis since infancy and had atopic dermatitis. Bronchiectasis developed at age 18 years, esophageal stenosis, possibly caused by Candida esophagitis, developed at age 19 years, and iron-deficiency anemia developed in her late twenties. She suffered from herpes zoster infection 3 times at ages 11, 30, and 33 years. The boy had oral thrush and onychomycosis and was diagnosed with chronic mucocutaneous candidiasis at age 1 year. Herpes zoster infection developed at age 4 years. Ectopic expression of the STAT1 G384D mutant in HeLa cells demonstrated that G384D was associated with gain of function due to impaired STAT1 dephosphorylation. Anti-CD3D (186790)/anti-CD28 (186760) or Candida stimulation of peripheral blood mononuclear cells and CD4 (186940)-positive T cells from the patients resulted in significantly reduced production of IL17A (603149) and IL22 (605330), but not IL17F (606496).
In 2 unrelated Danish men (P7 and P8) with immunodeficiency 31A (IMD31A; 614892) manifest as adult-onset herpes simplex encephalitis (HSE) after age 60, Mork et al. (2015) identified a heterozygous c.796G-A transition (c.796G-A, NM_007315.3) in the STAT1 gene, resulting in a val266-to-ile (V266I) substitution. The mutation, which was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing, was present at a low frequency (0.0020) in the ExAC database. Patient peripheral blood mononuclear cells showed significantly lower beta-interferon (IFNB1; 147640), CXCL10 (147310), and TNFA (191160) responses to HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. Patient cells did not have impaired responses to the TLR3 (603029) agonist poly(I;C). The findings suggested that STAT1 variants may contribute to HSE susceptibility in adults. The patients had no other significant infections.
In a 23-year-old woman with IMD31C (614162), Hartono et al. (2018) detected heterozygosity for a c.1165G-C transversion that resulted in a val389-to-leu (V389L) substitution by whole-exome sequencing. Stimulation of pretransplant patient fibroblasts with interferon-gamma (IFNG; 147570) showed hyperphosphorylation of STAT1 compared to control fibroblasts. Luciferase reporter assay demonstrated gain-of-function transcriptional activity in response to IFNG. This mutation was not present in the gnomAD database on January 10, 2020 (Hamosh, 2020).
In a 17-year-old boy with immunodeficiency-31C (IMD31C; 614162), Stellacci et al. (2019) identified a de novo heterozygous c.1398C-G transversion (c.1398C-G, NM_007315.3) in the STAT1 gene, resulting in a ser466-to-arg (S466R) substitution at a highly conserved residue in the DNA-binding domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells transfected with the mutation showed lower levels of the mutant protein compared to controls, but the mutant protein had a prolonged half-life and did not undergo accelerated degradation. After interferon treatment, the mutant protein demonstrated increased phosphorylation of tyr701 compared to controls, suggesting a possible positive effect of the mutant protein on downstream signaling through increased expression of interferon type I-stimulated genes. Analysis of patient peripheral blood showed an upregulation of both type I and type II interferon signatures associated with increased mRNA levels of interferon-induced genes; these changes were also observed in transfected HEK293 cells. Based on theses data, Stellacci et al. (2019) suggested that the disorder associated with upregulated STAT1 function (a gain-of-function effect) could be considered an interferonopathy. In addition to recurrent infections and autoimmune features, the patient showed brain calcifications, arthritis, pericarditis, leukopenia, thrombocytopenia, and low C3 levels, resembling an interferonopathy.
Boisson-Dupuis, S., Kong, X.-F., Okada, S., Cypowyj, S., Puel, A., Abel, L., Casanova, J.-L. Inborn errors of human STAT1: allelic heterogeneity governs diversity of immunological and infectious phenotypes. Curr. Opin. Immun. 24: 364-378, 2012. [PubMed: 22651901] [Full Text: https://doi.org/10.1016/j.coi.2012.04.011]
Braumuller, H., Wieder, T., Brenner, E., Assmann, S., Hahn, M., Alkhaled, M., Schilbach, K., Essmann, F., Kneilling, M., Griessinger, C., Ranta, F., Ullrich, S., and 18 others. T-helper-1-cell cytokines drive cancer into senescence. Nature 494: 361-365, 2013. [PubMed: 23376950] [Full Text: https://doi.org/10.1038/nature11824]
Chapgier, A., Boisson-Dupuis, S., Jouanguy, E., Vogt, G., Feinberg, J., Prochnicka-Chalufour, A., Casrouge, A., Yang, K., Soudais, C., Fieschi, C., Santos, O. F., Bustamante, J., and 10 others. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2: e131, 2006. Note: Electronic Article. [PubMed: 16934001] [Full Text: https://doi.org/10.1371/journal.pgen.0020131]
Chapgier, A., Wynn, R. F., Jouanguy, E., Filipe-Santos, O., Zhang, S., Feinberg, J., Hawkins, K., Casanova, J.-L., Arkwright, P. D. Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J. Immun. 176: 5078-5083, 2006. [PubMed: 16585605] [Full Text: https://doi.org/10.4049/jimmunol.176.8.5078]
Chen, X., Vinkemeier, U., Zhao, Y., Jeruzalmi, D., Darnell, J. E., Jr., Kuriyan, J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93: 827-839, 1998. [PubMed: 9630226] [Full Text: https://doi.org/10.1016/s0092-8674(00)81443-9]
Copeland, N. G., Gilbert, D. J., Schindler, C., Zhong, Z., Wen, Z., Darnell, J. E., Jr., Mui, A. L.-F., Miyajima, A., Quelle, F. W., Ihle, J. N., Jenkins, N. A. Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics 29: 225-228, 1995. [PubMed: 8530075] [Full Text: https://doi.org/10.1006/geno.1995.1235]
Darnell, J. E., Jr., Kerr, I. M., Stark, G. M. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415-1421, 1994. [PubMed: 8197455] [Full Text: https://doi.org/10.1126/science.8197455]
Dupuis, S., Dargemont, C., Fieschi, C., Thomassin, N., Rosenzweig, S., Harris, J., Holland, S. M., Schreiber, R. D., Casanova, J.-L. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293: 300-303, 2001. [PubMed: 11452125] [Full Text: https://doi.org/10.1126/science.1061154]
Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., Al-Mohsen, I. Z., Al-Jumaah, S., Yang, K., Chapgier, A., Eidenschenk, C., Eid, P., Al Ghonaium, A., Tufenkeji, H., Frayha, H., Al-Gazlan, S., Al-Rayes, H., Schreiber, R. D., Gresser, I., Casanova, J.-L. Impaired response to interferon-gamma/beta and lethal viral disease in human STAT1 deficiency. Nature Genet. 33: 388-391, 2003. [PubMed: 12590259] [Full Text: https://doi.org/10.1038/ng1097]
Durbin, J. E., Hackenmiller, R., Simon, M. C., Levy, D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84: 443-450, 1996. [PubMed: 8608598] [Full Text: https://doi.org/10.1016/s0092-8674(00)81289-1]
Fu, X.-Y., Kessler, D. S., Veals, S. A., Levy, D. E., Darnell, J. E., Jr. ISGF3, the transcriptional activator induced by interferon alpha consists of multiple interacting polypeptide chains. Proc. Nat. Acad. Sci. 87: 8555-8559, 1990. [PubMed: 2236065] [Full Text: https://doi.org/10.1073/pnas.87.21.8555]
Haddad, B., Pabon-Pena, C. R., Young, H., Sun, W. H. Assignment of STAT1 to human chromosome 2q32 by FISH and radiation hybrids. Cytogenet. Cell Genet. 83: 58-59, 1998. [PubMed: 9925928] [Full Text: https://doi.org/10.1159/000015126]
Hamosh, A. Personal Communication. Baltimore, Md. 01/10/2020.
Hartman, S. E., Bertone, P., Nath, A. K., Royce, T. E., Gerstein, M., Weissman, S., Snyder, M. Global changes in STAT target selection and transcription regulation upon interferon treatments. Genes Dev. 19: 2953-2968, 2005. [PubMed: 16319195] [Full Text: https://doi.org/10.1101/gad.1371305]
Hartono, S. P., Vargas-Hernandez, A., Ponsford, M. J., Chinn, I. K., Jolles, S., Wilson, K., Forbes, L. R. Novel STAT1 gain-of-function mutation presenting as combined immunodeficiency. J. Clin. Immunol. 38: 753-756, 2018. [PubMed: 30317461] [Full Text: https://doi.org/10.1007/s10875-018-0554-3]
Hikasa, M., Yamamoto, E., Kawasaki, H., Komai, K., Shiozawa, K., Hashiramoto, A., Miura, Y., Shiozawa, S. p21(waf1/cip1) is down-regulated in conjunction with up-regulation of c-Fos in the lymphocytes of rheumatoid arthritis patients. Biochem. Biophys. Res. Commun. 304: 143-147, 2003. [PubMed: 12705898] [Full Text: https://doi.org/10.1016/s0006-291x(03)00574-6]
Ihle, J. N., Kerr, I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11: 69-74, 1995. [PubMed: 7716810] [Full Text: https://doi.org/10.1016/s0168-9525(00)89000-9]
Ihle, J. N. Cytokine receptor signalling. Nature 377: 591-594, 1995. [PubMed: 7566171] [Full Text: https://doi.org/10.1038/377591a0]
Ihle, J. N. STATs: signal transducers and activators of transcription. Cell 84: 331-334, 1996. [PubMed: 8608586] [Full Text: https://doi.org/10.1016/s0092-8674(00)81277-5]
Kaplan, D. H., Shankaran, V., Dighe, A. S., Stockert, E., Aguet, M., Old, L. J., Schreiber, R. D. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Nat. Acad. Sci. 95: 7556-7561, 1998. [PubMed: 9636188] [Full Text: https://doi.org/10.1073/pnas.95.13.7556]
Kim, S., Koga, T., Isobe, M., Kern, B. E., Yokochi, T., Chin, Y. E., Karsenty, G., Taniguchi, T., Takayanagi, H. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 17: 1979-1991, 2003. [PubMed: 12923053] [Full Text: https://doi.org/10.1101/gad.1119303]
Kong, X.-F., Ciancanelli, M., Al-Hajjar, S., Alsina, L., Zumwalt, T., Bustamante, J., Feinberg, J., Audry, M., Prando, C., Bryant, V., Kreins, A., Bogunovic, D., Halwani, R., Zhang, X.-X., Abel, L., Chaussabel, D., Al-Muhsen, S., Casanova, J.-L., Boisson-Dupuis, S. A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood 116: 5895-5906, 2010. [PubMed: 20841510] [Full Text: https://doi.org/10.1182/blood-2010-04-280586]
Kosaka, H., Yoshimoto, T., Yoshimoto, T., Fujimoto, J., Nakanishi, K. Interferon-gamma is a therapeutic target molecule for prevention of postoperative adhesion formation. Nature Med. 14: 437-441, 2008. [PubMed: 18345012] [Full Text: https://doi.org/10.1038/nm1733]
Leopold Wager, C. M., Hole, C. R., Wozniak, K. L., Olszewski, M. A., Wormley, F. L., Jr. STAT1 signaling is essential for protection against Cryptococcus neoformans infection in mice. J. Immun. 193: 4060-4071, 2014. [PubMed: 25200956] [Full Text: https://doi.org/10.4049/jimmunol.1400318]
Li, W., Hofer, M. J., Songkhunawej, P., Jung, S. R., Hancock, D., Denyer, G., Campbell, I. L. Type I interferon-regulated gene expression and signaling in murine mixed glial cells lacking signal transducers and activators of transcription 1 or 2 or interferon regulatory factor 9. J. Biol. Chem. 292: 5845-5859, 2017. [PubMed: 28213522] [Full Text: https://doi.org/10.1074/jbc.M116.756510]
Liu, L., Okada, S., Kong, X.-F., Kreins, A. Y., Cypowyj, S., Abhyankar, A., Toubiana, J., Itan, Y., Audry, M., Nitschke, P., Masson, C., Toth, B., and 54 others. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208: 1635-1648, 2011. [PubMed: 21727188] [Full Text: https://doi.org/10.1084/jem.20110958]
Meraz, M. A., White, J. M., Sheehan, K. C. F., Bach, E. A., Rodig, S. J., Dighe, A. S., Kaplan, D. H., Riley, J. K., Greenlund, A. C. Campbell, D., Carver-Moore, K., DuBois, R. N., Clark, R., Aguet, M., Schreiber, R. D. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84: 431-442, 1996. [PubMed: 8608597] [Full Text: https://doi.org/10.1016/s0092-8674(00)81288-x]
Mork, N., Kofod-Olsen, E., Sorensen, K. B., Bach, E., Orntoft, T. F., Ostergaard, L., Paludan, S. R., Christiansen, M., Mogensen, T. H. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 16: 552-566, 2015. [PubMed: 26513235] [Full Text: https://doi.org/10.1038/gene.2015.46]
Mowen, K. A., Tang, J., Zhu, W., Schurter, B. T., Shuai, K., Herschman, H. R., David, M. Arginine methylation of STAT1 modulates IFN-alpha/beta-induced transcription. Cell 104: 731-741, 2001. [PubMed: 11257227] [Full Text: https://doi.org/10.1016/s0092-8674(01)00269-0]
Ramana, C. V., Chatterjee-Kishore, M., Nguyen, H., Stark, G. R. Complex roles of Stat1 in regulating gene expression. Oncogene 19: 2619-2627, 2000. [PubMed: 10851061] [Full Text: https://doi.org/10.1038/sj.onc.1203525]
Rodriguez, J. J., Wang, L.-F., Horvath, C. M. Hendra virus V protein inhibits interferon signaling by preventing STAT1 and STAT2 nuclear accumulation. J. Virol. 77: 11842-11845, 2003. Note: Erratum: J. Virol. 77: 13457 only, 2003. [PubMed: 14557668] [Full Text: https://doi.org/10.1128/jvi.77.21.11842-11845.2003]
Rosenzweig, S. D., Holland, S. M. Defects in the interferon-gamma and interleukin-12 pathways. Immunol. Rev. 203: 38-47, 2005. [PubMed: 15661020] [Full Text: https://doi.org/10.1111/j.0105-2896.2005.00227.x]
Sampaio, E. P., Hsu, A. P., Pechacek, J., Bax, H. I., Dias, D. L., Paulson, M. L., Chandrasekaran, P., Rosen, L. B., Carvalho, D. S., Ding, L., Vinh, D. C., Browne, S. K., and 23 others. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J. Allergy Clin. Immun. 131: 1624-1634, 2013. [PubMed: 23541320] [Full Text: https://doi.org/10.1016/j.jaci.2013.01.052]
Schindler, C., Fu, X.-Y., Improta, T., Aebersold, R., Darnell, J. E., Jr. Proteins of transcription factor ISGF-3: one gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc. Nat. Acad. Sci. 89: 7836-7839, 1992. [PubMed: 1502203] [Full Text: https://doi.org/10.1073/pnas.89.16.7836]
Shankaran, V., Ikeda, H., Bruce, A. T., White, J. M., Swanson, P. E., Old, L. J., Schreiber, R. D. IFN-gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410: 1107-1111, 2001. [PubMed: 11323675] [Full Text: https://doi.org/10.1038/35074122]
Smeekens, S. P., Plantinga, T. S., van de Veerdonk, F. L., Heinhuis, B., Hoischen, A., Joosten, L. A. B., Arkwright, P. D., Gennery, A., Kullberg, B. J., Veltman, J. A., Lilic, D., van der Meer, J. W. M., Netea, M. G. STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS ONE 6: e29248, 2011. Note: Electronic Article. [PubMed: 22195034] [Full Text: https://doi.org/10.1371/journal.pone.0029248]
Soltesz, B., Toth, B., Shabashova, N., Bondarenko, A., Okada, S., Cypowyj, S., Abhyankar, A., Csorba, G., Tasko, S., Sarkadi, A. K., Mehes, L., Rozsival, P., Neumann, D., Chernyshova, L., Tulassay, Z., Puel, A., Casanova, J.-L., Sediva, A., Litzman, J., Marodi, L. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. J. Med. Genet. 50: 567-578, 2013. [PubMed: 23709754] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101570]
Spagnoli, A., Torello, M., Nagalla, S. R., Horton, W. A., Pattee, P., Hwa, V., Chiarelli, F., Roberts, C. T., Jr., Rosenfeld, R. G. Identification of STAT-1 as a molecular target of IGFBP-3 in the process of chondrogenesis. J. Biol. Chem. 277: 18860-18867, 2002. [PubMed: 11886859] [Full Text: https://doi.org/10.1074/jbc.M200218200]
Stellacci, E., Moneta, G. M., Bruselles, A., Barresi, S., Pizzi, S., Torre, G., De Benedetti, F., Tartaglia, M., Insalaco, A. The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies. Clin. Genet. 96: 585-589, 2019. [PubMed: 31448411] [Full Text: https://doi.org/10.1111/cge.13632]
Takeda, A., Hamano, S., Yamanaka, A., Hanada, T., Ishibashi, T., Mak, T. W., Yoshimura, A., Yoshida, H. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J. Immun. 170: 4886-4890, 2003. [PubMed: 12734330] [Full Text: https://doi.org/10.4049/jimmunol.170.10.4886]
Takeuchi, K., Kadota, S., Takeda, M., Miyajima, N., Nagata, K. Measles virus V protein blocks interferon (IFN)-alpha/beta but not IFN-gamma signaling by inhibiting STAT1 and STAT2 phosphorylation. FEBS Lett. 545: 177-182, 2003. [PubMed: 12804771] [Full Text: https://doi.org/10.1016/s0014-5793(03)00528-3]
Tsumura, M., Okada, S., Sakai, H., Yasunaga, S., Ohtsubo, M., Murata, T., Obata, H., Yasumi, T., Kong, X.-F., Abhyankar, A., Heike, T., Nakahata, T., and 9 others. Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. Hum. Mutat. 33: 1377-1387, 2012. [PubMed: 22573496] [Full Text: https://doi.org/10.1002/humu.22113]
Uzel, G., Sampaio, E. P., Lawrence, M. G., Hsu, A. P., Hackett, M., Dorsey, M. J., Noel, R. J., Verbsky, J. W., Freeman, A. F., Janssen, E., Bonilla, F. A., Pechacek, J., and 11 others. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J. Allergy Clin. Immun. 131: 1611-1623, 2013. [PubMed: 23534974] [Full Text: https://doi.org/10.1016/j.jaci.2012.11.054]
van de Veerdonk, F. L., Plantinga, T. S., Hoischen, A., Smeekens, S. P., Joosten, L. A. B., Gilissen, C., Arts, P., Rosentul, D. C., Carmichael, A. J., Smits-van-der Graaf, C. A. A., Kullberg, B. J., van der Meer, J. W. M., Lilic, D., Veltman, J. A., Netea, M. G. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. New Eng. J. Med. 365: 54-61, 2011. [PubMed: 21714643] [Full Text: https://doi.org/10.1056/NEJMoa1100102]
Wang, J., Schreiber, R. D., Campbell, I. L. STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-alpha in the central nervous system. Proc. Nat. Acad. Sci. 99: 16209-16214, 2002. [PubMed: 12461178] [Full Text: https://doi.org/10.1073/pnas.252454799]
Wang, W., Yin, Y., Xu, L., Su, J., Huang, F., Wang, Y., Boor, P. P. C., Chen, K., Wang, W., Cao, W., Zhou, X., Liu, P., van der Laan, L. J. W., Kwekkeboom, J., Peppelenbosch, M. P., Pan, Q. Unphosphorylated ISGF3 drives constitutive expression of interferon-stimulated genes to protect against viral infections. Sci. Signal. 10: eaah4248, 2017. Note: Electronic Article. [PubMed: 28442624] [Full Text: https://doi.org/10.1126/scisignal.aah4248]
Wesemann, D. R., Qin, H., Kokorina, N., Benveniste, E. N. TRADD interacts with STAT1-alpha and influences interferon-gamma signaling. Nature Immun. 5: 199-207, 2004. Note: Erratum: Nature Immun. 5: 344 only, 2004. [PubMed: 14730360] [Full Text: https://doi.org/10.1038/ni1025]
Xiao, L., Naganawa, T., Obugunde, E., Gronowicz, G., Ornitz, D. M., Coffin, J. D., Hurley, M. M. Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. J. Biol. Chem. 279: 27743-27752, 2004. [PubMed: 15073186] [Full Text: https://doi.org/10.1074/jbc.M314323200]
Xu, W., Edwards, M. R., Borek, D. M., Feagins, A. R., Mittal, A., Alinger, J. B., Berry, K. N., Yen, B., Hamilton, J., Brett, T. J., Pappu, R. V., Leung, D. W., Basler, C. F., Amarasinghe, G. K. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16: 187-200, 2014. [PubMed: 25121748] [Full Text: https://doi.org/10.1016/j.chom.2014.07.008]
Yamamoto, K., Kobayashi, H., Arai, A., Miura, O., Hirosawa, S., Miyasaka, N. cDNA cloning, expression and chromosome mapping of the human STAT4 gene: both STAT4 and STAT1 genes are mapped to 2q32.2-q32.3. Cytogenet. Cell Genet. 77: 207-210, 1997. [PubMed: 9284918] [Full Text: https://doi.org/10.1159/000134578]
Yamazaki, Y., Yamada, M., Kawai, T., Morio, T., Onodera, M., Ueki, M., Watanabe, N., Takada, H., Takezaki, S., Chida, N., Kobayashi, I., Ariga, T. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J. Immun. 193: 4880-4887, 2014. [PubMed: 25288569] [Full Text: https://doi.org/10.4049/jimmunol.1401467]