STAT6 joins the gain-of-function club

In 2000, Daniel et al1Daniel C. Salvekar A. Schindler U. A gain-of-function mutation in STAT6.J Biol Chem. 2000 May 12; 275: 14255-14259Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar uncovered a gain-of-function (GOF) mutation in the signal transducer and activator of transcription 6 (STAT6) SH2 domain during in vitro mutagenesis and predicted that “such a mutation, if found in vivo, could cause genetic predisposition for atopic disease.” The article by Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar in this issue of the Journal of Allergy and Clinical Immunology is the latest of a series of recent reports describing heterozygous GOF variants in STAT6 that are associated with severe early-onset allergic disease.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar characterize a single proband with a heterozygous STAT6 missense variant (c.1114G>A, p.E372K) leading to severe refractory atopic dermatitis, food allergies, eosinophilia, and elevated IgE level associated with connective tissue abnormalities and short stature. Collectively, 4 reports have now described 13 families with 21 affected patients, including with de novo mutations and autosomal dominant inheritance, clearly highlighting STAT6-GOF as a new and distinct monogenic primary atopic disorder. STAT6 is the major transcription factor mediating the biologic effects of IL-4 and IL-13, and it has been implicated in the pathophysiology of many allergic diseases. Cytokine receptor engagement triggers phosphorylation of Janus kinases (JAKs) leading to STAT phosphorylation, which requires tight negative feedback loops. The inducible suppressor of cytokine signaling (SOCS) family of proteins, nuclear dephosphorylation, and direct STAT competition have been shown as regulatory mechanisms. STAT activation requires dimerization, followed by nuclear transport and DNA binding. Not surprisingly, dominant heterozygous pathogenic variants have emerged as a common mechanism of JAK-STAT–related immune dysregulation disorders, now including STAT6. The main clinical features (Fig 1, A2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 6Li J. Rodriguez J.P. Niu F. Pu M. Wang J. Hung L.W. et al.Structural basis for DNA recognition by STAT6.Proc Natl Acad Sci U S A. 2016; 113: 13015-13020Crossref PubMed Scopus (38) Google Scholar) of STAT6-GOF observed in the 21 affected patients reported2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar include the following: (1) severe early-onset atopic disease in all patients, including treatment-refractory eczematous dermatitis, food or drug allergies, asthma, and severe or recurrent anaphylaxis, accompanied by markedly elevated serum IgE levels and hypereosinophilia; (2) gastrointestinal features present in three-quarters of patients, most of whom have severe eosinophilic gastrointestinal inflammation, and less commonly, diarrhea or protein-losing enteropathy in 1 family; (3) mild recurrent skin and respiratory infections present in half of patients; (4) in roughly one-third of patients, skeletal abnormalities mimicking those observed in autosomal dominant hyper-IgE syndrome caused by heterozygous STAT3 mutations with a dominant negative effect, namely osteoporosis, pathologic fractures, joint hyperextensibility, and/or vascular anomalies; and (5) with short stature, which is present in roughly 40% of patients across the cohort. Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar noted a 10-year-old boy with significant lymphadenopathy, whereas the child reported by Takeuchi et al4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar displayed large polypoid nodules in the intestinal tract. Notably, an older subject in Sharma et al3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar had recurrent B-cell lymphomas. Given the strong association of somatic STAT6-activating mutations with follicular lymphoma and other B-cell malignancies,7Mentz M. Keay W. Strobl C.D. Antoniolli M. Adolph L. Heide M. et al.PARP14 is a novel target in STAT6 mutant follicular lymphoma.Leukemia. 2022; 36: 2281-2292Crossref PubMed Scopus (1) Google Scholar particular attention should be given to a possible malignancy risk as the cohort ages. Nonatopic clinical features in STAT6-GOF syndrome include skeletal abnormalities similar to those observed in patients with dominant negative defects in the gp130/STAT3 pathway.8Milner J.D. Primary atopic disorders.Annu Rev Immunol. 2020; 38: 785-808Crossref PubMed Scopus (26) Google Scholar The STAT proteins often have intersecting negative feedback loops, in which alterations in 1 STAT protein can lead to cross-regulation of the others, which may explain overlapping clinical features. For example, SOCS3 is a known negative regulator of JAK3-STAT5 downstream of the growth hormone receptor. Notably, Sharma et al3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar demonstrated that cells of patients with STAT6-GOF had elevated SOCS3 expression similar to that in patients with STAT3-GOF. However, Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar documented normal pSTAT5 signaling following stimulation and identified very low growth hormone levels rather than reduced pSTAT5 signaling. Thus, further direct ex vivo testing and single-cell transcriptional analysis may provide clarification. The immune features typically associated with defects in the gp130/STAT3 pathway—namely, organ-specific autoimmunity, autoimmune cytopenias, chronic mucocutaneous candidiasis, mycobacterial or fungal infections, or hypogammaglobulinemia—were noticeably absent in patients with STAT6-GOF mutations. T cells secreting TH2 cytokines (IL-4, IL-5, and IL-13) were significantly expanded, and TH2 cell markers, including GATA3 and IL4R-α, showed increased expression, likely in a feedforward loop with increased serum IL-4 level.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar observed lower TH1 and TH17 cell marker expression by effector and regulatory T cells in their patient, who was the only patient to have invasive infections with bacterial pneumonia, bacteremia, and soft-tissue abscesses; however, immunophenotyping and testing of humoral immunity did not identify functional defects. Other investigators demonstrated no decrease in patient TH1 or TH17 cell frequencies, consistent with the lack of serious invasive infections or candidiasis in the corresponding cases.3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar,5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Most of the reported STAT6-GOF germline variants cluster in the DNA-binding domain (Fig 1, B).2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Isolated variants in the linker domain, in the SH2 domain, and near the critical Y641 residue required for dimerization were also described,3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar but no activating variants were found in other domains. STAT6 has strong genetic constraint,9Rapaport F. Boisson B. Gregor A. Béziat V. Boisson-Dupuis S. Bustamante J. et al.Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance.Proc Natl Acad Sci U S A. 2021; 118e2001248118Crossref Scopus (22) Google Scholar similar to that of STAT1 or STAT3, but curiously, STAT6 loss-of-function mutation has not been found. On the basis of existing structural models, several authors demonstrated that the STAT6-GOF variants clustered around the protein-DNA interface and highlighted a neutral or negative-to-positive charge amino acid change.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar,3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar,5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Enhanced binding of STAT6 to DNA was therefore a commonly proposed mechanism. STAT6 does not require phosphorylation for nuclear trafficking, and nuclear accumulation reflects DNA binding. In support of this, Takeuchi et al4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar revealed STAT6 nuclear enrichment in the absence of cytokine stimulation in the affected proband, with augmented pSTAT6 following stimulation. Unlike other STAT proteins, STAT6 has a unique N4 binding site, and there is growing evidence that new gene targets accompany these STAT6-GOF variants.5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,6Li J. Rodriguez J.P. Niu F. Pu M. Wang J. Hung L.W. et al.Structural basis for DNA recognition by STAT6.Proc Natl Acad Sci U S A. 2016; 113: 13015-13020Crossref PubMed Scopus (38) Google Scholar Further mechanistic studies will be needed across multiple variants, but clearly, these GOF variants can drive both cytokine independence and aberrant transcription. Several other mechanisms for STAT6-GOF variants have been proposed.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Augmented, although only mildly, levels of STAT6 protein were observed in 1 subject.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar Although spontaneous STAT6 phosphorylation was not observed either in circulating TH2 cells or in lymphoblastoid cell lines created from affected patients,2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar STAT6 hyperphosphorylation was found following IL-4 stimulation.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar,4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In contrast, Sharma et al3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar found lymphoblastoid cell lines from several patients to have comparable peak phosphorylation but delayed dephosphorylation in all but 1 kindred. The cell type, level of cytokine receptor, ratio of pSTAT6 to total STAT6, particular variant tested, and time course are each experimental factors to consider, making comparisons across studies challenging. Intriguingly, Baris et al2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar noted that patient treatment with ruxolitinib for 1 month reversed the hyperphosphorylation state following IL-4 stimulation. Both JAK inhibition and IL-4/IL-13 inhibition with dupilumab worked remarkably well to treat the patients’ cutaneous and allergic symptoms, suggesting that altered IL-4 signaling is a dominant feature of this disorder.2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Lastly, an important practical consideration raised by Sharma et al3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar involves clinical “red flags” to indicate when STAT6-GOF syndrome, and thus genetic testing, should be considered. Atopic disease is increasingly common in the industrialized world.10R. Pawankar, G.W. Canonica, S.T. Holgate and R.F. Lockey, eds. World Allergy Organization (WAO) White Book on Allergy 2011-2012: Executive Summary. 2011, World Allergy Organization; Wisconsin, USA.Google Scholar It may be unrealistic, and arguably unnecessary, to perform genetic testing in all individuals with moderate-to-severe atopy. In general practice, many atopic patients present with multiple red flags, including early-onset eczema, asthma, allergies, mild peripheral blood eosinophilia, and elevated serum IgE level. Thus, we would propose that the symptoms highlighted by the 4 aforementioned authors2Baris S. Benamar M. Chen Q. Catak M.C. Martinez-Blanco M. Wang M. et al.Severe Allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.J Allergy Clin Immunol. 2023; 152: 182-194.e7Abstract Full Text Full Text PDF Scopus (3) Google Scholar, 3Sharma M. Leung D. Momenilandi M. Jones L.C.W. Pacillo L. James A.E. et al.Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.J Exp Med. 2023; 220e20221755Crossref PubMed Scopus (7) Google Scholar, 4Takeuchi I. Yanagi K. Takgeda S. Uchiyama T. Igarashi A. Motomura K. et al.STAT6 gain-of-function variant exacerbates multiple allergic symptoms.J Allergy Clin Immunol. 2023; 151: 1402-1409.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Suratannon N. Ittiwut C. Dik W.A. Ittiwut R. Meesilpavikkai K. Israsena N. et al.A germline STAT6 gain-of-function variant is associated with early-onset allergies.J Allergy Clin Immunol. 2023; 151: 565-571Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar as red flags should focus on the more extreme features of this condition, such as the following early-onset multisystem atopic disease refractory to standard therapies; thickened skin suggesting dermal fibrosis; severe eosinophilic gastrointestinal disease; and atypical features such as short stature and connective tissue, skeletal, or vascular anomalies (Fig 1, A). Genetic testing should be used if JAK inhibitors or other immunosuppressive therapies are being considered to rule out other monogenic atopic disorders that are associated with significantly increased susceptibilities to infection, such as heterozygous STAT3 mutations with dominant negative effect. One limitation, of course, is the fact that the reported STAT6-GOF phenotype has been biased by accrual of severely allergic individuals. Would it make sense to sequence moderately atopic individuals in addition to examining environmental factors or to search for epigenetic modifications? Ultimately, there likely exists a spectrum of disease, from more common STAT6 variants to more severe GOF variants, and further work will be needed to determine how these studies will change therapies. In the meantime, let us welcome STAT6 to the GOF club. Disclosure of potential conflict of interest: K. Chen has been a speaker and/or consultant for Horizon Therapeutics and Takeda Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6Journal of Allergy and Clinical ImmunologyVol. 152Issue 1PreviewA number of monogenic inborn errors of immunity (IEI) give rise to allergic dysregulation as a prominent disease manifestation.1,2 Originally, heterozygous loss-of-function mutations in STAT3 were first identified as the cause of autosomal dominant form of the hyper IgE syndrome (HIES).3 Afterward, DOCK8 deficiency was discovered to cause the autosomal recessive form of the disease.4,5 Subsequently, other genetic causes of HIES have been identified, encompassing mutations in PGM3, ZNF341, IL6ST, IL6R, ERBIN, TGFBR1, TGFBR2, and CARD11. Full-Text PDF