{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:03:32Z","timestamp":1791594212122,"version":"4.3.4"},"reference-count":11,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Gain-of-function (GOF) mutations in\n                      <jats:italic>STAT1<\/jats:italic>\n                      cause a combined immunodeficiency characterized by chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmunity. Mutations in the DNA-binding domain (DBD) have previously been associated with poor outcomes, but the contributions of specific variants to clinical phenotype remain unexplored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a systematic literature review to identify patients with confirmed\n                      <jats:italic>STAT1<\/jats:italic>\n                      GOF mutations, integrating new cases with a previously reported international cohort. Clinical and genetic data were analyzed at both domain and mutation level to define genotype-phenotype correlations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 533 unique patients from 36 countries were identified, harboring 135 distinct mutations. As previously reported, DBD mutations were associated with increased risk of systemic infections, bronchiectasis, autoimmunity, and reduced survival. However, mutation-level stratification revealed that the T385M variant accounted for much of this effect. Compared with both other DBD mutations and mutations elsewhere in\n                      <jats:italic>STAT1<\/jats:italic>\n                      , T385M conferred significantly higher rates of infection, bronchiectasis, autoimmunity, and premature death (p &amp;lt; 0.001). Conversely, certain coiled-coil (CC) domain mutations, such as R274Q, were associated with milder disease and improved survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that the adverse prognosis previously ascribed to DBD mutations in\n                      <jats:italic>STAT1<\/jats:italic>\n                      GOF is predominantly driven by the T385M variant. Mutation-specific, rather than domain-level, stratification is therefore essential for accurate risk assessment and clinical management. In particular, patients predicted to have severe disease, such as those with the T385M mutation should be considered early for curative interventional therapies such as stem cell transplant or gene therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1717692","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:30:01Z","timestamp":1764311401000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The T385M STAT1 gain-of-function mutation confers the most severe disease outcomes"],"prefix":"10.3389","volume":"16","author":[{"given":"Robert","family":"Torrance","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"McKenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"McDowell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"O\u2019Callaghan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesmeen","family":"Maimaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana S.","family":"Albuquerque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Pearce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma C.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan O.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20110958","article-title":"Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis","volume":"208","author":"Liu","year":"2011","journal-title":"J Exp Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3154","DOI":"10.1182\/BLOOD-2015-11-679902","article-title":"Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype","volume":"127","author":"Toubiana","year":"2016","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMOA1100102","article-title":"STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis","volume":"365","author":"van de Veerdonk","year":"2011","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/S10875-020-00847-X","article-title":"Human STAT1 gain-of-function heterozygous mutations: chronic mucocutaneous candidiasis and type I interferonopathy","volume":"40","author":"Okada","year":"2020","journal-title":"J Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/PAI.13694","article-title":"DNA-Binding domain mutations confer severe outcome at an early age among STAT1 gain-of-function patients","volume":"33","author":"Scott","year":"2022","journal-title":"Pediatr Allergy Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.654406","article-title":"Clinical relevance of gain- and loss-of-function germline mutations in STAT1: A systematic review","volume":"12","author":"Zhang","year":"2021","journal-title":"Front 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HSCT in STAT1 gain-of-function disease following JAK inhibition bridging","volume":"1","author":"Buddingh","year":"2025","journal-title":"J Hum Immun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/J.JACI.2017.03.049","article-title":"Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations","volume":"141","author":"Leiding","year":"2018","journal-title":"J Allergy Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1717692\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:30:02Z","timestamp":1764311402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1717692\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":11,"alternative-id":["10.3389\/fimmu.2025.1717692"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1717692","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"article-number":"1717692"}}