{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:30:20Z","timestamp":1790857820281,"version":"4.1.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"vor","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council of Australia","award":["1176665"],"award-info":[{"award-number":["1176665"]}]},{"name":"National Health and Medical Research Council of Australia","award":["2017463"],"award-info":[{"award-number":["2017463"]}]},{"name":"Careers in Immunology Fellowship"},{"DOI":"10.13039\/100002570","name":"American Association of Immunologists","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002570","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scheinberg Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Signal transducer and activator of transcription 3 (STAT3) orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and\/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA-binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema, and enteropathy over a 35-year period.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In vitro demonstration of prolonged STAT3 activation due to delayed dephosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in the peripheral blood of patients with STAT3 gain-of-function syndrome. Identifying cellular biomarkers of disease provides a flow cytometric-based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cei\/uxaf005","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T17:07:52Z","timestamp":1737479272000},"source":"Crossref","is-referenced-by-count":6,"title":["Functional validation of a novel <i>STAT3<\/i> \u2018variant of unknown significance\u2019 identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects."],"prefix":"10.1093","volume":"219","author":[{"given":"Joseph","family":"Mackie","sequence":"first","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Suan","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"Clinical Immunogenomics Research Consortium of Australasia (CIRCA) , Darlinghurst, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"McNaughton","sequence":"additional","affiliation":[{"name":"Clinical Immunogenomics Research Consortium of Australasia (CIRCA) , Darlinghurst, NSW ,","place":["Australia"]},{"name":"Queensland Paediatric Immunology and Allergy Service, Queensland Children\u2019s Hospital , South Brisbane ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomeen","family":"Haerynck","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Infectious Diseases and Immunology, Ghent University Hospital , Ghent ,","place":["Belgium"]},{"name":"Primary Immunodeficiency Research Lab, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital , Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Clinical Immunogenomics Research Consortium of Australasia (CIRCA) , Darlinghurst, NSW ,","place":["Australia"]},{"name":"Department of Clinical Immunology and PathWest, Fiona Stanley Hospital , Murdoch, WA ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Guerin","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy S","family":"Ma","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]},{"name":"Clinical Immunogenomics Research Consortium of Australasia (CIRCA) , Darlinghurst, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-5180","authenticated-orcid":false,"given":"Stuart G","family":"Tangye","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney , Kensington, NSW ,","place":["Australia"]},{"name":"Clinical Immunogenomics Research Consortium of Australasia (CIRCA) , Darlinghurst, NSW 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