Autosomal-dominant hyper-IgE syndrome (AD-HIES) is characterized by chronic mucocutaneous candidiasis, recurrent sinopulmonary pneumonias, noninflammatory atopic dermatitis, extremely high levels of serum IgE, and non-immunological manifestations affecting the musculoskeletal and vascular systems. Most cases are caused by heterozygous dominant-negative (DN) variants in STAT3. Approximately 150 unique pathogenic STAT3 variants have been identified in hundreds of ethnically diverse kindreds who present with AD-HIES. Most variants are missense, affecting the DNA binding, SH2, and transactivation domains of STAT3. Remarkably, very few pathogenic variants affecting the N-terminal domain (NTD) have been identified. Here, we present a patient, P1, with a novel variant affecting the STAT3 NTD (R31Q) who presented with disseminated invasive aspergillosis affecting the brain and lung, bronchiectasis, and high serum IgE, but lacking non-immune disease manifestations. Biochemical analyses established that R31Q reduces expression and transcriptional activity of STAT3 and exhibits negative dominance on wild-type (WT) STAT3. We implemented Alphafold3 to predictively model the impact this variant had on STAT3 dimer formation and tested our hypotheses using in vitro biomolecular tests. We found that this variant resulted in enhanced basal dimerization with WT STAT3, thus sequestering STAT3 WT/STAT3 R31Q dimers in the cytosol, dampening nuclear translocation and subsequent transcriptional activity. Lymphocytes from P1 exhibited some typical defects observed in canonical STAT3 LOF/DN HIES (reduced memory B cells, mucosal associated invariant T [MAIT] cells, and Th17 cytokines). However, P1’s naïve B cells had only a partial impairment in in vitro Ig secretion to IL-21. More striking were intact Th2 cells and circulating T follicular helper (Tfh) cells. Our findings reveal a hitherto unknown function of the NTD in regulating STAT3 dimer formation and function. This expands our understanding of JAK/STAT signaling, provides a novel biochemical mechanism of disease pathogenesis in STAT3 LOF/DN HIES, and extends the clinical spectrum of patients with STAT3 variants.
