Disruption of the N-terminal domain in a STAT3 hyper-IgE syndrome variant causes disease by sequestering STAT3 in the cytoplasm

Autosomal-dominant hyper-IgE syndrome (HIES) is characterized by chronic mucocutaneous candidiasis, recurrent sinopulmonary complications, noninflammatory atopic dermatitis, high amounts of serum IgE, and nonimmunological manifestations affecting the musculoskeletal and vascular systems. Most cases are caused by heterozygous loss-of-function, dominant-negative (LOF/DN) variants that affect the DNA binding, SH2, or transactivation domains of STAT3. Here, we report a patient with a unique STAT3 allele affecting the STAT3 N-terminal domain (R31Q), who presented with disseminated invasive aspergillosis affecting the brain and lung, bronchiectasis, and high serum IgE but lacked nonimmune disease manifestations. Biochemical analyses in cell lines demonstrated that R31Q reduced the abundance and transcriptional activity of STAT3 and caused it to exhibit negative dominance on wild-type (WT) STAT3. This was due to preferential STAT3 R31Q dimerization with STAT3 WT , sequestration of STAT3 WT :STAT3 R31Q dimers in the cytosol, and a reduction in STAT3 nuclear translocation and transcriptional activity. Lymphocytes from the patient exhibited some typical defects observed in canonical STAT3 LOF/DN HIES, such as reduced memory B cells, MAIT cells, and T H 17 cytokines. However, naïve B cells from this patient had only a partial impairment in immunoglobulin secretion induced by interleukin-21 (IL-21) in vitro, and the patient had normal numbers of T H 2 cells and circulating T FH cells. Our findings reveal that the N-terminal domain regulates STAT3 dimer formation and function and provide a previously unknown biochemical mechanism of disease pathogenesis in STAT3 LOF/DN HIES.