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In this study, we evaluate the functional relevance of a previously undescribed heterozygous\n                    <jats:italic>STAT3<\/jats:italic>\n                    variant in a patient with clinical findings of STAT3\u2010HIES. Flow cytometry, quantitative real\u2010time PCR, pull\u2010down assays, native PAGE, DNA\u2010binding ELISA, and 3D\u2010structural data analysis were performed. Genetic analysis identified the heterozygous\n                    <jats:italic>STAT3<\/jats:italic>\n                    variant NM_139276.2:c.2127G&gt;C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3\u2010HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild\u2010type STAT3 in STAT3\u2010deficient cells indicated a dominant\u2010negative effect by the mutation. Analysis of 3D\u2010structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C\u2010terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3\u2010HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation.\n                  <\/jats:p>","DOI":"10.1002\/eji.70015","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T05:54:48Z","timestamp":1753768488000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Signal Transducer and Activator of Transcription 3 (STAT3) Variant p.K709N Causes Hyper\u2010IgE Syndrome Likely by Impaired STAT3\u2010Dimer Formation"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0717-3508","authenticated-orcid":false,"given":"Beate","family":"Hagl","sequence":"first","affiliation":[{"name":"Translational Immunology, Faculty of Medicine University of Augsburg  Augsburg Germany"},{"name":"Translational Immunology in Environmental Medicine, School of Medicine and Health Technical University of Munich  Munich Germany"},{"name":"Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Comprehensive Pneumology Center (CPC\u2010M), German Center of Lung Research (DZL) Munich Germany"},{"name":"Department of Pediatrics, TUM University Hospital, School of Medicine and Health Technical University of Munich  Munich Germany"},{"name":"Department of Pediatrics, Dr. Von Hauner Children's Hospital LMU University Hospital, LMU Munich  Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt D.","family":"Spielberger","sequence":"additional","affiliation":[{"name":"Translational Immunology in Environmental Medicine, School of Medicine and Health Technical University of Munich  Munich Germany"},{"name":"Department of Pediatrics, Dr. Von Hauner Children's Hospital LMU University Hospital, LMU Munich  Munich 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