HGNC Approved Gene Symbol: STAT2
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:56,341,597-56,360,107 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Immunodeficiency 44 | 616636 | Autosomal recessive | 3 |
| Pseudo-TORCH syndrome 3 | 618886 | Autosomal recessive | 3 |
The STAT2 gene encodes a subunit of ISGF3 (see ISGF3G, 147574), a multiprotein transcription factor that is activated in the cytoplasm after attachment of interferon-alpha (see IFNA1, 147660) to the cell surface (summary by Fu et al., 1992).
By screening a human cDNA library with probes based on peptide sequences of the 113-kD ISGF3 subunit, Fu et al. (1992) cloned STAT2. The deduced 851-amino acid protein contains 3 major helices in its N-terminal region, followed by heptad leucine repeats that may form a coiled-coil structure, an SH2-like domain, and a C-terminal acidic domain. Northern blot analysis detected a 4.8-kb transcript in HeLa cells.
Sugiyama et al. (1996) cloned full-length mouse Stat2 and 2 alternatively spliced forms that encode the same truncated protein. RT-PCR detected all 3 variants in several mouse tissues, although the full-length form was most abundant and was expressed in all tissues examined. RT-PCR of a human hepatoblastoma cell line revealed full-length STAT2 and only 1 STAT2 splice variant. The short form of human STAT2 encodes a protein in which the 231 C-terminal amino acids are replaced by 32 novel amino acids. It lacks half of the SH2 domain, the tyrosine phosphorylation site required for dimerization and DNA binding, and the C-terminal activation domain.
The STAT proteins have the dual function of signal transduction and activation of transcription as part of a phosphorylation cascade. The binding of IFNA1 to its receptor leads to activation of ISGF3, a DNA-binding complex composed of STAT1 (600555), STAT2, and p48 (ISGF3G). Bluyssen and Levy (1997) showed that STAT2 forms stable homodimers which complex with p48 and bind to the interferon-stimulated response element (ISRE). The authors concluded that assembly of the ISGF3 complex involves p48 functioning as an adaptor protein to recruit STAT1 and STAT2 to the ISRE. STAT2 is a potent transactivator in this complex, but lacks the ability to bind DNA directly.
Banninger and Reich (2004) found that unphosphorylated STAT2 constitutively shuttled in and out of the nucleus in human fibrosarcoma cell lines. Unphosphorylated STAT2 was imported into the nucleus via association with IRF9 (ISGF3G), but a STAT2 C-terminal nuclear export signal directed the return of the STAT2-IRF9 complex to the cytoplasm. Following tyrosine phosphorylation in response to IFN signaling, STAT2 dimerized with STAT1, resulting in a conformational change that directed nuclear localization. Banninger and Reich (2004) concluded that STAT2 does not accumulate in the nucleus in the absence of STAT1.
Stimulation of cells by IFNA results in phosphorylation of both STAT1 and STAT2, producing STAT1 homodimers and STAT1/STAT2 heterodimers. Hartman et al. (2005) identified numerous STAT1 and STAT2 gene targets on chromosome 22 following IFN stimulation of HeLa cells, and they found that STAT1/STAT2 heterodimers bound sites not occupied by STAT1 homodimers.
Takeuchi et al. (2003) found that measles virus V protein blocked IFNA/IFN-beta (IFNB1; 147640)-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 (102582). 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.
Using single-cell RNA sequencing in mouse bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharide (LPS) to investigate expression variability on a genomic scale, Shalek et al. (2013) observed extensive and theretofore unobserved bimodal variation in mRNA abundance and splicing patterns. They found that hundreds of key immune genes are bimodally expressed across cells, even genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrated heterogeneity between cells. Shalek et al. (2013) identified a module of 137 highly variable yet coregulated antiviral response genes. Using cells from knockout mice, Shalek et al. (2013) showed that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7 (605047). This finding demonstrated that while some of the observed bimodality could be attributed to closely related, yet distinct, known maturity states of BMDCs, other portions reflected differences in the usage of key regulatory circuits.
Shahni et al. (2015) demonstrated that STAT2 is a regulator of mitochondrial fission. Studies of cells from patients with STAT2 loss of function mutations suggested that STAT2 deficiency results in DRP1 (DNM1L; 603850) inactivation, which causes defective mitochondrial fission and relative mitochondrial hyperfusion. STAT2 was identified as an additional phosphorylase capable of phosphorylating DRP1 on Ser616.
Blaszczyk et al. (2015) found that IFN-alpha (see IFNA1, 147660) response in human and mouse STAT1 knockout cells was diminished and correlated with diminished STAT2 phosphorylation. Overexpression of STAT2 in STAT1 knockout cells restored the IFN-alpha response, confirming this result. In STAT1 knockout cells overexpressing STAT2, STAT2 and IRF9 (147574) interacted, and the STAT2/IRF9 complex was responsible for the IFN-alpha response in the absence of STAT1. Comparative analysis of transcriptional responses in genes upregulated by both STAT2/IRF9 and ISGF3 in these cells implied functional overlap between STAT2/IRF9 and ISGF3, especially for the potential of generating an IFN-alpha-induced antiviral response. Moreover, STAT2/IRF9 was found to regulate the expression of IFN-stimulated response element (ISRE)-independent ISGs. Antiviral assays found that STAT2/IRF9 mediated an antiviral response similar to that of ISGF3 against encephalomyocarditis virus (EMCV) and vesicular stomatitis Indiana virus (VSV), providing further evidence for functional overlap between STAT2/IRF9 and ISGF3 in the antiviral response.
Li et al. (2017) compared the expression of genes in murine mixed glial cell cultures (MGCs) that lacked Stat1, Stat2, or Irf9 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-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.
Yan et al. (1995) reported the complete genomic sequence and characterization of the promoter region and exonic structure of the human STAT2 gene. It contains 24 exons and has an imperfect ISRE, consistent with its weak transcriptional induction by IFNA1. In comparison with STAT1, Yan et al. (1995) found considerable conservation throughout a 700-amino acid coding region, and the genomic structure is largely conserved.
Gross (2015) mapped the STAT2 gene to chromosome 12q13.3 based on an alignment of the STAT2 sequence (GenBank BC051284) with the genomic sequence (GRCh38).
Immunodeficiency 44
In 5 affected members of a consanguineous kindred with immunodeficiency-44 (IMD44; 616636), Hambleton et al. (2013) identified a homozygous splice site mutation in the STAT2 gene (600556.0001). In vitro studies of patient fibroblasts showed increased susceptibility to infection with viruses and a complete failure of the type I interferon response; this defect was rescued after transduction with wildtype STAT2.
In 2 sibs with IMD44, Shahni et al. (2015) identified a homozygous nonsense mutation in the STAT2 gene (C612X; 600556.0002). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Patient skeletal muscle and fibroblasts showed dense elongated mitochondria which were corrected by transduction of wildtype STAT2, and knockdown of STAT2 in control cells resulted in a 4-fold increase in mitochondrial length. Mitochondria from the patient reported by Hambleton et al. (2013) showed similar abnormalities. Patient fibroblasts showed undetectable STAT2 protein levels and increased levels of several outer and inner mitochondrial membrane fusion proteins, such as MFN1 (608506), MFN2 (608507), and OPA1 (605290), consistent with an increase in mitochondrial mass. Patient cells also showed abnormal phosphorylation of DNM1L (603850), resulting in DNM1L inactivity, impaired mitochondrial fission, and relative hyperfusion. Phosphorylation of STAT1 (600555) was also disrupted, confirming a disturbance in the alpha-interferon pathway. Finally, STAT2-deficient patient cells showed impaired apoptosis in response to alpha-interferon compared to controls. The report suggested a link between innate immunity and mitochondrial dysfunction.
In a patient, born to consanguineous parents, with IMD44, Freij et al. (2021) identified a homozygous nonsense mutation in the STAT2 gene (R667X; 600556.0005). STAT2 expression was absent in patient fibroblasts. Patient cells exposed to interferon-alpha-2b failed to induce expression of interferon-stimulated genes, and patient cells exposed to encephalomyocarditis virus had decreased survival compared to wildtype, indicating a defective antiviral response.
Using whole-exome or whole-genome sequencing in an international cohort of 112 children less than 16 years of age who were hospitalized for COVID-19 pneumonia, Zhang et al. (2022) identified 1 patient (P1) with compound heterozygosity for a missense and a nonsense variant, S613F and Q685X, in the STAT2 gene. Compound heterozygosity was confirmed by family segregation analysis. Further studies showed that these variants both resulted in production of only small amounts of protein, confirming loss of function. Phosphorylation of STAT2 in response to stimulation with IFN-alpha-2b (see 147562) was abolished, whereas response to IFN-gamma (147570) remained intact. Cells from this patient did not control SARS-CoV-2 viral replication normally. No pathogenic variants in STAT2 were seen among the control population, which consisted of 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia. The authors noted that recessive deficiencies of type I IFN immunity such as this might underlie approximately 10% of pediatric hospitalizations for COVID-19 pneumonia.
Pseudo-TORCH Syndrome 3
In 2 brothers, born of consanguineous Pakistani parents, with pseudo-TORCH syndrome-3 (PTORCH3; 618886), Duncan et al. (2019) identified a homozygous missense mutation in the STAT2 gene (R148W; 600556.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found only in the heterozygous state at a very low frequency in the gnomAD database. STAT2 protein expression was unaffected in patient cells. RNA and RT-PCR analysis of patient blood showed increased IFN-stimulated gene (ISG) gene expression, consistent with a type I interferonopathy. Basal and induced production of beta-interferon (IFNB1; 147640) and alpha-interferon (IFNA1; 147660) were similar to controls, although these samples were acquired during treatment. Patient cells and STAT2-null cells transduced with the mutation showed a similar heightened sensitivity to IFNA1, consistent with an abnormally enhanced response upon exposure to interferon, rather than constitutive activation of STAT2. The abnormalities were associated with prolonged IFNAR (107450) signaling in patient cells, but not in parental cells carrying the heterozygous mutation, which the authors noted is unusual for gain-of-function mutations. Further in vitro studies showed that the R148W mutation impaired the interaction of STAT2 with the negative regulator USP18 (607057), resulting in desensitization to the negative regulation normally conferred by USP18. Knockdown of USP18 in control cells resulted in prolonged STAT2 phosphorylation, recapitulating the phenotype of patient cells. In contrast, USP18 was unable to suppress IFN-alpha signaling in patient cells; knockdown of USP18 in patients cells also had no effect, indicating insensitivity to USP18. The findings were consistent with an inability of patient cells to properly restrain IFNAR signaling, which results in an inflammatory disease consistent with a type I interferonopathy. Duncan et al. (2019) noted that the loss of negative regulation of IFNAR signaling, due to the STAT2 mutation, behaves as a recessive trait with an overall gain-of-function effect on the IFN signaling pathway.
In a boy, born of consanguineous Moroccan parents, with PTORCH3, Gruber et al. (2020) identified a homozygous missense mutation in the STAT2 gene (R148Q; 600556.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in the unaffected mother; paternal DNA was not available. The authors noted that the R148 residue is highly conserved in mammals, but not in rodents. Prolonged IFN1 stimulation of patient cells and of STAT2-null cells transduced with the mutation resulted in increased expression of interferon-stimulated genes (ISGs) compared to controls, consistent with a gain-of-function effect. Notably, expression of wildtype STAT2 resulted in normalization of the defects, showing that biallelic mutation is required for the effect. Immunoprecipitation studies in patient fibroblasts showed reduced ability of R148Q STAT2 to recruit USP18 to the IFNAR2 (602376) receptor complex, although affinity between mutant STAT2 and USP18 appeared to be normal. Patient cells were unable to attenuate signaling in response to IFN1 even in the presence of USP18, suggesting that USP18 was functionally null, perhaps due to a trafficking defect of USP18 to the IFNAR receptor. Gruber et al. (2020) noted that homozygous gain-of-function mutations are rare, and suggested that they must disrupt negative regulatory processes to be pathogenic, as in this case.
Mendez et al. (2012) reported that STAT2 haplotype N, which has a sequence that closely matches that of Neanderthal STAT2, is not carried by sub-Saharan Africans, but that it has an average frequency of 5% in Eurasians and 54% in Melanesians. A neutrality test indicated that the high frequency in Melanesians is not a result of genetic drift alone. The authors identified nonsynonymous mutations in ERBB3 (190151), ESYT1, and STAT2, all of which are part of the same 250-kb introgressive haplotype, as candidate targets of positive selection in this population.
In 5 affected members of a consanguineous kindred with immunodeficiency-44 (IMD44; 616636), Hambleton et al. (2013) identified a homozygous G-to-C transversion (c.381+5G-C) in the STAT2 gene, predicted to destroy the donor splice site of intron 4. The mutation, which was not found in the Ensembl (release 67) database or in 218 ethnically matched controls, segregated with the disorder in the family. Studies of patient cells showed aberrant splicing of intron 4 and decreased transcript amounts, suggesting some nonsense-mediated mRNA decay, and patient fibroblasts showed no detectable STAT2 protein. In vitro studies of patient fibroblasts showed increased susceptibility to infection with viruses and a complete failure of the type I interferon response; this defect was rescued after transduction with wildtype STAT2.
In 2 sibs, born of unrelated Albanian parents, with immunodeficiency-44 (IMD44; 616636), Shahni et al. (2015) identified a homozygous c.1836C-A transversion in the STAT2 gene, resulting in a cys612-to-ter (C612X) substitution in the SH2 domain. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. The patients presented in infancy with severe neurologic deterioration following live attenuated viral immunization, and also had evidence of immune deficiency.
In 2 brothers, born of consanguineous Pakistani parents, with pseudo-TORCH syndrome-3 (PTORCH3; 618886), Duncan et al. (2019) identified a homozygous c.442C-T transition (c.442C-T, NM_005419.3) in the STAT2 gene, resulting in an arg148-to-trp (R148W) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found only in the heterozygous state at a very low frequency in the gnomAD database. STAT2 protein expression was unaffected in patient cells. RNA and RT-PCR analysis of patient blood showed increased IFN-stimulated gene (ISG) gene expression, consistent with a type I interferonopathy. Patient cells and STAT2-null cells transduced with the mutation showed a similar heightened sensitivity to IFNA1 (147660), consistent with an abnormally enhanced response upon exposure to interferon, rather than constitutive activation of STAT2. The abnormalities were associated with prolonged IFNAR (107450) signaling in patient cells, but not in parental cells carrying the heterozygous mutation, which the authors noted is unusual for gain-of-function mutations. Further in vitro studies showed that the R148W mutation impaired the interaction of STAT2 with the negative regulator USP18 (607057), resulting in desensitization to the negative regulation normally conferred by USP18. The findings were consistent with an inability of patient cells to properly restrain IFNAR signaling, which results in an inflammatory disease consistent with a type I interferonopathy. Duncan et al. (2019) noted that the loss of negative regulation of IFNAR signaling, due to the STAT2 mutation, behaves as a recessive trait with an overall gain-of-function effect on the IFN signaling pathway.
In a boy, born of consanguineous Moroccan parents, with pseudo-TORCH syndrome-3 (PTORCH3; 618886), Gruber et al. (2020) identified a homozygous c.443G-A transition in exon 5 of the STAT2 gene, resulting in an arg148-to-gln (R148Q) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in the unaffected mother; paternal DNA was not available. The authors noted that the R148 residue is highly conserved in mammals, but not in rodents. It was not present in the gnomAD database or in an in-house database of over 6,000 exomes. In vitro functional expression studies and studies of patient cells showed that prolonged IFN1 stimulation resulted in increased expression of interferon-stimulated genes (ISGs) compared to controls, consistent with a gain-of-function effect. Notably, expression of wildtype STAT2 resulted in normalization of the defects, showing that biallelic mutation is required for the effect. Immunoprecipitation studies in patient fibroblasts showed reduced ability of R148Q STAT2 to recruit USP18 (607057) to the IFNAR2 (602376) receptor complex, although affinity between mutant STAT2 and USP18 appeared to be normal. Patient cells were unable to attenuate signaling in response to IFN1 even in the presence of USP18, suggesting that USP18 was functionally null, perhaps due to a trafficking defect of USP18 to the IFNAR receptor.
In a patient, born to consanguineous parents, with immunodeficiency-44 (IMD44; 616636), Freij et al. (2021) identified a homozygous c.1999C-T transition in the STAT2 gene, resulting in an arg667-to-ter (R667X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was identified in heterozygous state in the parents and an unaffected sib. The mutation was not present in the gnomAD database. STAT2 expression was absent in patient fibroblasts. Patient cells exposed to interferon-alpha-2b overnight failed to induce expression of interferon-stimulated genes, indicating a defect of appropriate antiviral response.
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