Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: STAT6
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:57,095,408-57,111,362 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections | 620532 | Autosomal dominant | 3 |
The STAT6 gene encodes a transcription factor that plays an important role in the biology of allergic inflammation by mediating the effects of IL4 (147780), a key cytokine necessary for type 2 differentiation of CD4+ T cells (Th2) and B cells, cell proliferation, and class switching to IgE, as well as the effects of IL13 (147683), a cytokine linked to anaphylaxis (summary by Sharma et al., 2023).
STAT6 also plays an important role in the extracellular cytokine and virus-mediated immune response (summary by Gu et al., 2018).
By searching a database of expressed sequence tags (ESTs), Quelle et al. (1995) identified a number of expressed genes in the signal transducers and activators of a transcription (STAT) family. Human and murine full-length cDNA clones were obtained and sequenced. The sequence of the human cDNA was identical to the sequence published by Hou et al. (1994) for the interleukin-4-induced transcription factor (called by them IL4 Stat), while the murine STAT6 amino acid and nucleotide sequences reported by Quelle et al. (1995) were 83% and 84% identical to the human sequences, respectively.
By screening an embryonic lung fibroblast cDNA library with a wildtype STAT6 probe, Patel et al. (1998) identified 2 variant cDNAs, which they termed STAT6b and STAT6c, encoding an N-terminal 110-amino acid truncation and a 27-amino acid deletion in the SH2 domain, respectively. RNase protection analysis detected ubiquitous expression of all 3 variants with STAT6b expression greatest in spleen and STAT6c expression greatest in lung.
Patel et al. (1998) characterized the genomic structure and flanking regions of the human STAT6 gene. The gene spans 19 kb and contains 23 exons.
Copeland et al. (1995) found that 7 mouse Stat genes map in 3 clusters, with each cluster located on a different autosome. They suggested that the Stat family arose by a tandem duplication of the ancestral Stat gene, followed by dispersion of the linked loci to different chromosomes. They mapped Stat6 and Stat2 (600556) to the distal region of chromosome 10. During an analysis of NAB2 (602381), Svaren et al. (1997) obtained the sequence adjacent to this gene by PCR of genomic DNA. They found that the STAT6 gene is located unusually close to the NAB2 gene, such that the 3-prime ends of their mRNAs overlap. Since the human NAB2 gene was previously mapped to 12q13.3-q14.1, it is likely that STAT6 maps to the same position. By fluorescence in situ hybridization, Leek et al. (1997) mapped STAT6 to 12q13.
Using STAT6-specific antiserum, Quelle et al. (1995) demonstrated that STAT6 is rapidly tyrosine phosphorylated following stimulation of appropriate cell lines with IL4 (147780) or IL3 (147740), but is not detectably phosphorylated following stimulation with IL2 (147680), IL12 (see IL12A; 161560), or erythropoietin (133170). In contrast, IL2, IL3, and erythropoietin induced the tyrosine phosphorylation of STAT5 (601511), while IL12 uniquely induced the tyrosine phosphorylation of STAT4 (600558). Inducible tyrosine phosphorylation of STAT6 required the membrane-distal region of the IL4 receptor alpha chain (IL4R; 147781). They found that this region of the receptor is not required for cell growth, demonstrating that STAT6 tyrosine phosphorylation does not contribute to mitogenesis.
Ghilardi et al. (1996) demonstrated that along with STAT3 (102582) and STAT5, STAT6 is involved in signaling from the leptin receptor (601007) and that this signaling is defective in the db/db mouse which carries a point mutation within the leptin receptor gene. Darnell (1996) reflected on STAT3, STAT5, and STAT6 as 'fat STATs,' i.e., the involvement of these 3 STATs, but not STAT1, STAT2, and STAT4, in the physiologic action of leptin (164160) as described by Ghilardi et al. (1996).
Kotanides and Reich (1996) identified a specific STAT6 DNA-binding target site in the promoter of the IL4R gene and showed that STAT6 activates IL4 gene expression via this site.
By functional analysis, Patel et al. (1998) determined that the STAT6b variant resembles an attenuated STAT6, but that the STAT6c variant inhibits IL4-mediated mitogenesis and cell surface antigen expression, and is not tyrosine phosphorylated.
Dickensheets et al. (1999) presented evidence that interferons inhibit IL4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS1 (603597).
Upregulation of proinflammatory cytokines in rheumatoid arthritis (RA; 180300) synovium and synovial fluid is a feature of active disease and intense inflammation. Antiinflammatory mediators are also present and activated in RA but fail to counterregulate the proinflammatory cytokines. Muller-Ladner et al. (2000) found that the IL4-STAT pathway is activated in patients with short-term (less than 1 year) and long-term (more than 2 years) RA and may contribute to downregulation of the immunologic activity in RA synovium.
Using immunocytochemistry, Christodoulopoulos et al. (2001) measured the expression of STAT6 in bronchial biopsy specimens from patients with atopic and nonatopic asthma and controls and found that there were more STAT6-immunoreactive cells in patients with atopic and with nonatopic asthma than in control subjects (p less than 0.0001 and 0.05, respectively). The authors also observed that there were fewer cells expressing STAT6 protein in nonatopic versus atopic asthma (p less than 0.0001) and concluded that reduced IL4R signaling, due to lower STAT6 expression, may be a feature of nonatopic asthma.
Mullings et al. (2001) investigated STAT6 expression in bronchial biopsy specimens or brushings from normal control or asthmatic subjects and found that the bronchial epithelium is the major site of STAT6 expression. Levels of expression in controls and subjects with mild asthma did not differ significantly; however, STAT6 expression was significantly increased in subjects with severe asthma (p less than 0.05).
Using confocal microscopy, Maldonado et al. (2004) found a random distribution of Tcrb (see 186930), Il4r, and Ifngr1 (107470) in fixed and permeabilized mouse naive T-helper lymphocytes (Thp) conjugated with mouse mature splenic dendritic cells (DCs). In cells fixed and permeabilized 30 minutes after conjugation of Thp and antigen-loaded DCs, the authors observed a calcium- and Ifng (147570)-dependent colocalization of Tcrb and Ifngr1, but not Il4r, at the Thp-DC interface. This observation was more apparent in the Th1-prone C57Bl/6 mouse strain than in the Th2-prone BALB/c strain. In the presence of Il4, but not Il10 (124092), Ifngr1 migration and copolarization was completely inhibited. In mice lacking the Il4r signaling molecule, Stat6, prevention of Tcrb/Ifngr1 copolarization was abolished. Maldonado et al. (2004) proposed that strong TCR signaling leads to accentuated IFNGR copolarization and the assembly of a Th1 signalosome, which is further stabilized by secretion of IFNG, unless an inhibitory signal, such as IL4 secretion and STAT6 activation, occurs and leads to the assembly of a Th2 signalosome. They concluded that the immunologic synapse may be involved in the control of cell fate decisions.
Following its proteolytic release and nuclear translocation, Low et al. (2006) found that the C-terminal tail of human polycystin-1 (PKD1; 601313) interacted with Stat6 and the coactivator P100 (602181) in canine kidney cells and stimulated Stat6-dependent gene expression. Under normal conditions, Stat6 localized to primary cilia of renal epithelial cells; however, cessation of apical fluid flow resulted in its nuclear translocation. Cyst-lining cells in autosomal dominant polycystic kidney disease exhibited elevated levels of nuclear STAT6, P100, and the polycystin-1 C-terminal tail. Exogenous expression of the human polycystin-1 C-terminal tail resulted in renal cyst formation in zebrafish embryos. Low et al. (2006) concluded that upregulation of the STAT6/P100 pathway by the polycystin-1 C-terminal tail leads to the cellular changes characteristic of renal cysts.
Most Toxoplasma gondii isolates in Europe and North America belong to 3 clonal lines, designated types I, II, and III. Using microarray, immunofluorescence, and Western blot analyses, Saeij et al. (2007) found that STAT3 and STAT6 were activated predominantly in fibroblasts infected with types I and III, rather than type II, T. gondii. They determined that the T. gondii Rop16 protein kinase mediated the strain-specific activation of STAT3 and STAT6. Saeij et al. (2007) noted that their results correlated with previous findings showing that type II T. gondii induces high levels of IL12A and IL12B (161561) secretion, whereas type I T. gondii induces STAT3 activation and prevents IL12 expression.
Using human and mouse cells, Chen et al. (2011) found that viruses or cytoplasmic nucleic acids triggered STING (TMEM173; 612374) to recruit STAT6 to the endoplasmic reticulum, where STAT6 was phosphorylated on ser407 by TBK1 (604834) and on tyr641 in a Janus kinase (see 147795)-independent manner. Phosphorylated STAT6 dimerized and translocated to the nucleus to induce genes involved in cell homing. Unlike the cell-type specific role of STAT6 in cytokine signaling, virus-induced STAT6 activation was detected in all cell types tested. Mice lacking Stat6 were susceptible to virus infection. Chen et al. (2011) concluded that STAT6 mediates immune signaling in response to cytokines at the plasma membrane and to virus infection at the endoplasmic reticulum.
Reese et al. (2014) found that helminth infection, characterized by the induction of Il4 (147780) and the activation of Stat6, reactivated murine gamma-herpesvirus infection in vivo. Il4 promoted viral replication and blocked the antiviral effects of Ifng by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. Il4 also reactivated human Kaposi sarcoma-associated herpesvirus from latency in cultured cells. Exogenous Il4 plus blockade of Ifng reactivated latent murine gamma-herpesvirus infection in vivo, suggesting a '2-signal' model for viral reactivation. Thus, Reese et al. (2014) concluded that chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status.
In the context of virus-helminth coinfection, Osborne et al. (2014) tested whether helminths induce potent immunomodulatory effects through direct regulation of host immunity or indirectly through eliciting changes in the microbiota. Helminth coinfection resulted in STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule associated with alternatively activated macrophages, could partially restore antiviral immunity. Osborne et al. (2014) concluded that these data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
By Western blot analysis, Gu et al. (2018) showed that expression of STAT6 was reduced during the early infection and lytic cycle of Kaposi sarcoma-associated herpesvirus (KSHV) due to expression of the KSHV transcription factor RTA. RTA interacted with STAT6 through its C-terminal transactivation domain and mediated degradation of STAT6 via the proteasomal and lysosomal pathways. Mutation analysis revealed RTA-induced degradation of STAT6 was independent of ubiquitylation of K108 and K398 or phosphorylation of Y641 on STAT6. Instead, RTA acted as an E3 ubiquitin ligase and promoted K48- and K63-linked ubiquitylation of STAT6 for its degradation. Knockdown analysis showed that STAT6 inhibited TRIML2 (620480) expression. STAT6 bound to a binding site in the TRIML2 promoter for inhibition. However, inhibition was released by KSHV infection, resulting in increased RTA expression and expression of a ubiquitylated form of TRIML2 that prolonged cell survival and virion production. The ubiquitin-modified TRIML2 was required for reactivation of the lytic cycle and contributed to virion production. STAT6 degradation and ubiquitylated TRIML2 appeared to be essential for lytic activation of herpesviruses, as the same results were obtained during reactivation of the lytic cycle in other human herpesviruses.
NAB2/STAT6 Gene Fusion in Solitary Fibrous Tumors
Using whole-exome sequencing, Chmielecki et al. (2013) identified fusion of the NAB2 (602381) and STAT6 genes in 7 of 17 solitary fibrous tumors (SFTs). Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors (55%). Fusion analysis of approximately 713 unique tumor-normal pairs from 5 tumor types did not identify any fusions involving these genes, suggesting that the NAB2/STAT6 fusion may be unique to SFTs.
Following the identification of a gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 in a recurrent SFT, Robinson et al. (2013) identified a NAB2/STAT6 fusion gene in all of 51 SFTs using transcriptome sequencing and RT-PCR combined with capillary sequencing. The NAB2/STAT6 fusion was present regardless of the anatomic site of origin or malignant versus benign status. Expression of NAB2/STAT6 fusion protein was confirmed in SFTs. The predicted fusion products harbored the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2/STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR responsive genes. Proliferation could be inhibited by small interfering RNA (siRNA) knockdown of EGR1 expression. Robinson et al. (2013) concluded their studies established the NAB2/STAT6 fusion as the defining driver mutation of SFT and provided an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
Hyper-IgE Syndrome 6, Autosomal Dominant, with Recurrent Infections
In 16 patients from 10 unrelated families with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified heterozygous missense mutations in the STAT6 gene (see, e.g., 601512.0001-601512.0005). The mutations, which were found by exome sequencing, trio-based exome sequencing, or next-generation sequencing, segregated with the disorder in an autosomal dominant manner in 3 families; mutations in the other 7 probands occurred de novo. Six of the mutations occurred in the DNA-binding domain, 5 at asp419 and 1 at glu382. In vitro studies of HEK293 cells transfected with the mutations showed that they caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. Transcriptome analysis of 2 of the mutations (D419G, 601512.0001 and E382Q, 601512.0004) in transfected cells showed increased expression of known STAT6 target genes, including IL4R (147781), CISH (602441), and XBP1 (194355). The data also indicated increased enrichment of T2 helper cell (Th2) drivers after stimulation and increased enrichment of proliferation pathways for D419G, consistent with its known oncogenic activity. Although patient lymphocytes did not show increased STAT6 phosphorylation either at baseline or in response to IL4 stimulation, there was variably delayed dephosphorylation compared to controls. Patient lymphocytes showed skewing towards Th2 pathway activity as assessed by flow cytometry and transcriptome analysis, consistent with activation of the STAT6 signaling pathway. In particular, patient CD4+ T cells showed increased expression of IL4R. Additional in vitro studies showed that treatment with JAK inhibitor ruxolitimib and the anti-IL4R dupilumab in mutation-carrying HEK293 cells resulted in decreased STAT6 phosphorylation and activation at baseline and after IL4 stimulation. Overall, the findings indicated that the STAT6 mutations identified in these patients caused a gain-of-function effect with inappropriate activation of STAT6 signaling.
In a 10-year-old boy, born of consanguineous parents, with HIES6, Baris et al. (2023) identified a de novo heterozygous missense mutation in the STAT6 gene (E372K; 601512.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, ExAC, and gnomAD. Detailed immunophenotyping of the patient showed dysregulation of the T-cell population, including increased circulating memory CD4+ T cells, decreased naive CD4+ T cells, and increased levels of Th2 CD4+ T cells and Th2-skewed Treg cells. Patient CD4+ T cells showed mildly increased STAT6 expression, and functional studies showed hyperphosphorylation and enhanced activation of STAT6 after IL4 stimulation compared to controls, consistent with a gain-of-function effect. There was also a high frequency of circulating IgE+ B cells and enhanced B-cell switching to IgE after IL4 stimulation. Transfection of the mutation into HEK293 cells confirmed a gain-of-function effect with upregulation of STAT6 phosphorylation and enhanced nuclear translocation of STAT6 after IL4 stimulation.
Polymorphisms Associated with Asthma, Atopy, and Related Traits
Duetsch et al. (2002) identified 13 single-nucleotide polymorphisms (SNPs) in STAT6 and tested them for linkage/association with asthma (600807) and related traits (total serum IgE level, eosinophil cell count, and SLOPE of the dose-response curve after bronchial challenge) in 108 Caucasian sib-pairs. Neither the SNPs nor a GT repeat in exon 1 showed linkage/association to asthma. A significant association was found between a SNP in intron 18 and an increase in total IgE levels (P = 0.0070), as well as an association between allele A4 of the GT repeat polymorphism and an increase in eosinophil cell count (P = 0.0010). The authors concluded that rather than contributing to the pathogenesis of asthma, the human STAT6 gene is more likely involved in the development of eosinophilia and changes in total IgE levels.
In a case-control association study of 214 white British subjects, Gao et al. (2004) demonstrated a significant association with asthma of an allele with a 13-GT repeat sequence in exon 1 of the STAT6 gene (OR, 1.52; 95% CI, 1.02-2.28; p = 0.027), whereas a 16-GT allele showed an inverse association with asthma (p = 0.018). Furthermore, individuals with the 13-GT allele had higher IgE levels compared with individuals with the 16-GT allele (p = 0.004). Transient transfection assays of different alleles revealed significantly higher transcriptional activity with the 13-GT allele compared to the 16-GT allele in Jurkat, HMC-1, and BEAS-2B cell lines. Gao et al. (2004) suggested that the GT repeat polymorphism of the STAT6 gene contributes to susceptibility to atopic asthma and total serum IgE levels, and that variation in the length of the GT repeat sequence influences the regulation of promoter activity.
Several studies have shown linkage of 12q13-q24 with atopy (see 147050)-related phenotypes. STAT6 is 1 of the candidate genes in this region, because of its involvement in Th2 cell differentiation, recruitment, and effector function. Studying a population-based cross-sectional cohort of 1,407 German adults, Weidinger et al. (2004) evaluated 6 polymorphisms of STAT6 for evidence of association with serum IgE levels and atopic disease. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showed odds ratios of 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles of 50%, 60%, and 90%, respectively.
Kuperman et al. (2002) developed mice conditionally expressing STAT6 only in the lung epithelium and demonstrated that these mice were protected from all pulmonary effects of IL13 (147683), a critical mediator of allergic asthma. Reconstitution of STAT6 only in epithelial cells was sufficient for IL13-induced airway hyperreactivity and mucus production in the absence of inflammation, fibrosis, or other lung pathology.
Bour-Jordan et al. (2003) showed that T cells from double-knockout mice deficient in Ctla4 (123890) and Stat6 were skewed toward a Th2 phenotype in vitro and in vivo by bypassing the need for Stat6. Instead, induction of Gata3 (131320) occurred in vitro and Cd4 (186940)-positive cells migrated to peripheral tissues in vivo. In addition, T-cell receptor crosslinking induced a relative increase of Nfatc1 (600489) versus Nfatc2 (600490) nuclear translocation and enhanced NFKB (164011) activation compared with Stat6 -/- T cells. Bour-Jordan et al. (2003) proposed that CTLA4 regulates T-cell differentiation by controlling the overall strength of the T-cell activation signal, bypassing the cytokine dependency of Th2 differentiation.
Wang et al. (2004) noted that BALB/c mice are prone to develop Th2 rather than Th1 responses to antigen and are resistant to experimental myasthenia gravis (MG; 254200). However, they found that after immunization with muscle acetylcholine receptor (AChR; see 100725), BALB/c mice lacking Stat6 were susceptible to EMG and developed more anti-AChR antibodies and complement-fixing anti-AChR antibodies than wildtype or Stat4 -/- mice. Stat6 -/- mouse Cd4-positive T cells proliferated to AChR in a manner comparable to wildtype and Stat4 -/- mice, but Stat6 -/- mice had abundant AChR-specific Ifng-producing Th1 cells that were nearly absent in wildtype and Stat4 -/- mice. Wang et al. (2004) concluded that anti-AChR Th1 cells are important in MG pathogenesis.
Chen et al. (2011) reported that mice lacking Stat6 were susceptible to virus infection.
Rosen et al. (2013) investigated the role of Stat6 in oxazolone colitis, a murine model of ulcerative colitis (266600). Colitic wildtype mice had increased Stat6 phosphorylation in epithelial cells, T cells, macrophages, and NKT cells. Mice lacking Stat6 had reduced colitis and decreased induction of the pore-forming tight junction protein Cldn2 (300520). Likewise, STAT6 knockdown in human colon epithelial cells reduced CLDN2 induction. Wildtype mice, but not Stat6 -/- mice, had increased mRNA expression of the Th2-inducing cytokines Il33 (608678) and thymic stromal lymphopoietin (TSLP; 607003). Mesenteric lymph node (MLN) cells from Stat6 -/- mice with colitis exhibited reduced secretion of Il4, Il5 (147850), Il13, and Ifng. Il33 augmented secretion of Il5, Il6 (147620), Il13, and Ifng from both wildtype and Stat6 -/- MLN cells. Rosen et al. (2013) concluded that STAT6 is involved in the pathogenesis of ulcerative colitis and has important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
In 2 unrelated patients, a woman of Middle Eastern descent in her thirties (P1, family A) and a man of East Asian descent in his twenties (P6, family E) with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified a de novo heterozygous c.1256A-G transition (c.1256A-G, NM_001178079.2) in the STAT6 gene, resulting in an asp419-to-gly (D419G) substitution in the DNA-binding domain. The mutation, which was found by trio-based exome sequencing in both families, was not present in the gnomAD database. In vitro studies of HEK293 cells transfected with the mutation showed that it caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. Transcriptome analysis of cells expressing D419G showed increased expression of known STAT6 target genes, including IL4R (147781), CISH (602441), and XBP1 (194355). The data also indicated increased enrichment of T2 helper cell (Th2) drivers after stimulation and increased enrichment of proliferation pathways for D419G, consistent with its known oncogenic activity. Although patient lymphocytes did not show increased STAT6 phosphorylation either at baseline or in response to IL4 stimulation, there was delayed dephosphorylation compared to controls. Patient lymphocytes showed skewing towards Th2 pathway activity as assessed by flow cytometry and transcriptome analysis, consistent with activation of the STAT6 signaling pathway.
In an affected mother and son of Middle Eastern descent (P3 and P4, family C) with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified a heterozygous c.1255G-T transversion (c.1255G-T, NM_001178079.2) in the STAT6 gene, resulting in an asp419-to-tyr (D419Y) substitution in the DNA-binding domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. In vitro studies of HEK293 cells transfected with the mutation showed that it caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. Transcriptome analysis of cells expressing D419G showed increased expression of known STAT6 target genes, including IL4R (147781), CISH (602441), and XBP1 (194355). The data also indicated increased enrichment of T2 helper cell (Th2) drivers after stimulation and increased enrichment of proliferation pathways for D419G, consistent with its known oncogenic activity. Patient lymphocytes did not show increased STAT6 phosphorylation either at baseline or in response to IL4 stimulation and there was not a delay in dephosphorylation compared to controls.
In a woman and her 2 sons of European descent (P7, P8, and P9, family F) with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified a heterozygous c.1255G-C transversion (c.1255G-C, NM_001178079.2) in the STAT6 gene, resulting in an asp419-to-his (D419H) substitution in the DNA-binding domain. The mutation, which was found by next-generation sequencing, segregated with the disorder in the family and was not present in the gnomAD database. In vitro studies of HEK293 cells transfected with the mutation showed that it caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. This family was also reported by Minskaia et al. (2023), who confirmed the gain-of-function effect in patient cells and HEK293 cells carrying the mutation. They observed elevated levels of STAT6 and phosphorylated STAT6 with increased transcription of downstream target genes. Minskaia et al. (2023) noted that one mutation carrier developed B-cell lymphoma at 49 years of age, and another died of anaphylaxis following ingestion of the NSAID ibuprofen.
In a 35-year-old man (P10, family G) with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified a de novo heterozygous c.1144G-C transversion (c.1144G-C, NM_001178079.2) in the STAT6 gene, resulting in a glu382-to-gln (E382Q) substitution in the DNA-binding domain. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. In vitro studies of HEK293 cells transfected with the mutation showed that it caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. Transcriptome analysis of cells transfected with the mutation showed increased expression of known STAT6 target genes, including IL4R (147781), CISH (602441), and XBP1 (194355).
In a mother and her 3 children (P13-P16, family J) with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Sharma et al. (2023) identified a heterozygous c.1555G-C transversion (c.1555G-C, NM_001178079.2) in the STAT6 gene, resulting in an asp519-to-his (D519H) substitution in the LD domain. The mutation, which was found by next-generation sequencing, segregated with the disorder in the family and was not present in the gnomAD database. In vitro studies of HEK293 cells transfected with the mutation showed that it caused a gain-of-function effect with increased promoter activity and phosphorylation of STAT6 at baseline and after stimulation compared to controls. Although patient lymphocytes did not show increased STAT6 phosphorylation either at baseline or in response to IL4 stimulation, there was delayed dephosphorylation compared to controls.
In a 10-year-old boy, born of consanguineous parents, with autosomal dominant hyper-IgE syndrome-6 with recurrent infections (HIES6; 620532), Baris et al. (2023) identified a de novo heterozygous c.1114G-A transition (c.1114G-A, NM_003153.5) in the STAT6 gene, resulting in a glu372-to-lys (E372K) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP, ExAC, and gnomAD. Patient CD4+ T cells showed mildly increased STAT6 expression, and functional studies showed hyperphosphorylation and enhanced activation of STAT6 after IL4 stimulation compared to controls, consistent with a gain-of-function effect.
Baris, S., Benamar, M., Chen, Q., Catak, M. C., Martinez-Blanco, M., Wang, M., Fong, J., Massaad, M. J., Sefer, A. P., Kara, A., Babayeva, R., Eltan, S. B., and 9 others. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. J. Allergy Clin. Immun. 152: 182-194.e7, 2023. [PubMed: 36758835] [Full Text: https://doi.org/10.1016/j.jaci.2023.01.023]
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