{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T02:44:51Z","timestamp":1788576291579,"version":"build-2803163510"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"35","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,8,29]]},"abstract":"<jats:p>\n                    The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (\n                    <jats:italic toggle=\"yes\">STAT3<\/jats:italic>\n                    ) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous\n                    <jats:italic toggle=\"yes\">STAT3<\/jats:italic>\n                    nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a\n                    <jats:italic toggle=\"yes\">Stat3<\/jats:italic>\n                    haploinsufficient (\n                    <jats:italic toggle=\"yes\">\n                      Stat3\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) mouse model in which we found that\n                    <jats:italic toggle=\"yes\">\n                      Stat3\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice had increased IgE serum levels, reduced T\n                    <jats:sub>H<\/jats:sub>\n                    17 cell differentiation, and were susceptible to a cutaneous\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in\n                    <jats:italic toggle=\"yes\">STAT3<\/jats:italic>\n                    with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adw2464","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T17:58:38Z","timestamp":1756490318000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-038X","authenticated-orcid":true,"given":"Virginia","family":"Andreani","sequence":"first","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3754-5541","authenticated-orcid":true,"given":"Aaron James","family":"Forde","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5860-6177","authenticated-orcid":true,"given":"Manfred","family":"Fliegauf","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Bressan","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"No\u00e9","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3139-1924","authenticated-orcid":true,"given":"Nils","family":"Ott","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8546-3247","authenticated-orcid":true,"given":"Shiva","family":"Saghafi","sequence":"additional","affiliation":[{"name":"Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8054-5603","authenticated-orcid":true,"given":"Larsen","family":"Vornholz","sequence":"additional","affiliation":[{"name":"TranslaTUM\u2013Central Institute for Translational Cancer Research, Technical University of Munich, Munich, Germany."},{"name":"Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-2944","authenticated-orcid":true,"given":"Sophie E.","family":"Isay","sequence":"additional","affiliation":[{"name":"TranslaTUM\u2013Central Institute for Translational Cancer Research, Technical University of Munich, Munich, Germany."},{"name":"Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8381-3597","authenticated-orcid":true,"given":"J\u00fcrgen","family":"Ruland","sequence":"additional","affiliation":[{"name":"TranslaTUM\u2013Central Institute for Translational Cancer Research, Technical University of Munich, Munich, Germany."},{"name":"Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."},{"name":"German Center for Infection Research (DZIF), partner site Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-7984","authenticated-orcid":true,"given":"Philipp","family":"Henneke","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"name":"Institute for Infection Prevention and Control, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"name":"CIBSS\u2013Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6897-6806","authenticated-orcid":true,"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"name":"CIBSS\u2013Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany."},{"name":"Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany."},{"name":"DZIF\u2013German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany."},{"name":"RESIST\u2013Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, 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