Signal transducer and activator of transcription 3 (STAT3) is a central transcription factor in cytokine signaling and plays a critical role in human immune homeostasis. Germline STAT3 variants can produce distinct clinical phenotypes depending on whether signaling is impaired or excessive. Loss-of-function/dominant-negative (LOF/DN) variants cause autosomal-dominant hyper-IgE syndrome (AD-HIES), whereas gain-of-function (GOF) variants are associated predominantly with immune dysregulation, autoimmunity, and lymphoproliferation.¹˒² A recently reported STAT3 variant, p.R31Q, expands the molecular spectrum of AD-HIES and highlights a mechanism involving abnormal STAT3 dimerization and cytoplasmic sequestration.³ 

STAT3 and autosomal-dominant hyper-IgE syndrome 

STAT3 mediates signals from several cytokines, including interleukin (IL)-6, IL-10, IL-21, and IL-23. Following cytokine stimulation, STAT3 is phosphorylated, forms dimers, translocates to the nucleus, and regulates transcription of genes involved in immune-cell differentiation and function. Disruption of this pathway particularly affects T-helper 17 (TH17) cell development, contributing to susceptibility to bacterial and fungal infections.1,4 

AD-HIES is characterized by eczema, recurrent staphylococcal skin infections, recurrent pulmonary infections with structural lung damage, markedly elevated serum IgE, eosinophilia, and characteristic skeletal, dental, and vascular abnormalities. STAT3 mutations were established as the genetic basis of AD-HIES in 2007, with most pathogenic variants involving the DNA-binding, Src homology 2 (SH2), or transactivation domains.4,5 

The pathogenic mechanism is generally dominant negative, rather than simple haploinsufficiency. Functional analyses have demonstrated that many heterozygous STAT3 variants interfere with the activity of the normal STAT3 protein. A comprehensive analysis showed that the majority of tested in-frame and out-of-frame STAT3 variants associated with AD-HIES exhibited negative dominance, indicating that mutant STAT3 proteins can actively impair the function of their normal counterparts.6 

STAT3R31Q: An alternative mechanism of dominant-negative activity 

The newly described STAT3R31Q variant is particularly notable because it affects the N-terminal domain, rather than the domains classically associated with AD-HIES. The patient carrying this variant had disseminated invasive aspergillosis involving the brain and lung, bronchiectasis, and markedly elevated serum IgE, but lacked several of the characteristic nonimmune manifestations commonly observed in STAT3-HIES.3  

Functional investigations demonstrated reduced abundance and transcriptional activity of STAT3R31Q. However, the critical finding was its interaction with wild-type STAT3. The mutant protein preferentially formed heterodimers with normal STAT3. These STAT3WT:STAT3R31Q complexes were retained in the cytoplasm, thereby limiting nuclear translocation of functional STAT3 and reducing cytokine-dependent transcription. Consequently, a single mutant allele was sufficient to impair STAT3 signaling despite the presence of one normal allele.3 

This mechanism provides an important explanation for dominant inheritance. The mutant protein does not merely reduce the amount of functional STAT3; instead, it interferes directly with the normal protein. Similar dominant-negative mechanisms have been demonstrated for other STAT3 variants, including variants affecting the DNA-binding and SH2 domains.6,7  

Clinical and biological implications 

The patient with STAT3R31Q demonstrated several immunological abnormalities typical of STAT3 deficiency, including reduced memory B cells, mucosa-associated invariant T cells, and TH17-associated cytokine responses. However, some immune compartments remained relatively preserved, illustrating the phenotypic variability that can accompany different STAT3 variants.3  

The findings also emphasize that STAT3-related disease exists on a functional spectrum rather than representing a single disorder. DN/LOF variants predominantly produce infectious susceptibility and the HIES phenotype, whereas GOF variants commonly cause early-onset autoimmunity, lymphoproliferation, and immune dysregulation.1,2,8 

Conclusion 

The identification of STAT3R31Q expands the molecular spectrum of AD-HIES and demonstrates a previously unrecognized role for the STAT3 N-terminal domain in regulating dimer formation. Preferential heterodimerization with wild-type STAT3 and cytoplasmic sequestration provide a mechanistic explanation for dominant-negative inheritance. These findings highlight the importance of functional characterization of rare STAT3 variants, particularly when genetic findings do not involve the classical STAT3 domains associated with HIES. 

References 

1. Mackie J, Ma CS, Tangye SG, Guerin A. The ups and downs of STAT3 function: too much, too little and human immune dysregulation. Clin Exp Immunol. 2023 Apr 25;212(2):107-116.  
2. Milner, J., Holland, S. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol 13, 635–648 (2013). 
3. Mackie J, Suan D, Langley DB, Avery DT, Rao G, Freeman AF, et al. Disruption of the N-terminal domain in a STAT3 hyper-IgE syndrome variant causes disease by sequestering STAT3 in the cytoplasm. Sci Signal. 2026;19(961):eaeg5302.  
4. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al.TAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608-1619.  
5. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T,Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007 Aug 30;448(7157):1058-62. 
6. Asano T, Khourieh J, Zhang P, Rapaport F, Spaan AN, Li J, et al.Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. J Exp Med. 2021 Aug 2;218(8):e20202592.  
7. Heimall J, Freeman A, Holland SM. Pathogenesis of hyper IgE syndrome. Clin Rev Allergy Immunol. 2010;38:32-38.  
8. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591-599.