{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:22:55Z","timestamp":1790900575994,"version":"4.1.0"},"reference-count":38,"publisher":"Rockefeller University Press","issue":"4","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,3]]},"abstract":"<jats:p>Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is characterized by the triad of hypoparathyroidism, Addison\u2019s disease, and chronic mucocutaneous candidiasis due to biallelic deleterious variants in AIRE. However, emerging evidence has established that some monoallelic variants affecting specific functional domains may also drive autoimmunity by negative dominance. Here, we describe a novel heterozygous AIRE variant, c.1010G&amp;gt;T (p.Cys337Phe), in three individuals from a Taiwanese-Singaporean family presenting with hypoparathyroidism, vitiligo, anemia, and ectodermal abnormalities, but not candidiasis. Functional studies confirmed AIREC337F is both loss-of-function and dominant negative to wild-type AIRE. Detection of neutralizing autoantibodies against type I IFNs, but not Th17 cytokines, further supported an APECED-like immunological profile and potentially explained the lack of infections in affected individuals. Like other dominant negative AIRE variants, AIREC337F localizes to the highly conserved PHD1 domain. Thus, our findings identify a novel pathogenic heterozygous AIRE variant and broaden the phenotype of autosomal dominant APECED. We also highlight the importance of functional validation in interpreting variants of unknown significance, particularly when disease prevalence and variant profiles differ from typical cohorts.<\/jats:p>","DOI":"10.70962\/jhi.20250151","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T06:21:32Z","timestamp":1757485292000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["A novel heterozygous pathogenic\n                    <i>AIRE<\/i>\n                    variant causing autoimmunity but not infectious susceptibility"],"prefix":"10.70962","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7558-5902","authenticated-orcid":true,"given":"Mounavi","family":"Vemula","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t3p7e85","id-type":"ROR","asserted-by":"publisher"}],"name":"Queensland Paediatric Immunology & Allergy Service, Queensland Children\u2019s Hospital 1 , South Brisbane,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4248-7737","authenticated-orcid":true,"given":"Bergithe E.","family":"Oftedal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zga2b32","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Bergen 2 Department of Clinical Science, , Bergen,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6497-9318","authenticated-orcid":true,"given":"Dorsa","family":"Iraji","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zga2b32","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Bergen 2 Department of Clinical Science, , Bergen,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-1214","authenticated-orcid":true,"given":"M\u00e9lanie","family":"Migaud","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 4 , Paris,","place":["France"]},{"id":[{"id":"https:\/\/ror.org\/05f82e368","id-type":"ROR","asserted-by":"publisher"}],"name":"Imagine Institute, Paris Cit\u00e9 University 5 , Paris,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9778-4344","authenticated-orcid":true,"given":"Christopher","family":"Richmond","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05p52kj31","id-type":"ROR","asserted-by":"publisher"}],"name":"Genetic Health Queensland, Royal Brisbane and Women\u2019s Hospital 8 , Herston,","place":["Australia"]},{"name":"School of Medicine, Griffith University 9 , Gold Coast,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5221-7303","authenticated-orcid":true,"given":"Syndia","family":"Lazarus","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05p52kj31","id-type":"ROR","asserted-by":"publisher"}],"name":"Royal Brisbane and Women\u2019s Hospital 10 Department of Diabetes and Endocrinology, , Herston,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7782-4169","authenticated-orcid":true,"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0420db125","id-type":"ROR","asserted-by":"publisher"}],"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University 3 , New York, NY,","place":["USA"]},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 4 , Paris,","place":["France"]},{"id":[{"id":"https:\/\/ror.org\/05f82e368","id-type":"ROR","asserted-by":"publisher"}],"name":"Imagine Institute, Paris Cit\u00e9 University 5 , Paris,","place":["France"]},{"name":"Howard Hughes Medical Institute 6 , New York, NY,","place":["USA"]},{"name":"Necker Hospital for Sick Children 7 Department of Pediatrics, , Paris,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0290-9589","authenticated-orcid":true,"given":"Anna","family":"Sullivan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t3p7e85","id-type":"ROR","asserted-by":"publisher"}],"name":"Queensland Paediatric Immunology & Allergy Service, Queensland Children\u2019s Hospital 1 , South Brisbane,","place":["Australia"]},{"name":"Clinical Immunogenomics Research Consortium Australasia (CIRCA) 11 , Darlinghurst,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-0323","authenticated-orcid":true,"given":"Anne","family":"Puel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0420db125","id-type":"ROR","asserted-by":"publisher"}],"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University 3 , New York, NY,","place":["USA"]},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 4 , Paris,","place":["France"]},{"id":[{"id":"https:\/\/ror.org\/05f82e368","id-type":"ROR","asserted-by":"publisher"}],"name":"Imagine Institute, Paris Cit\u00e9 University 5 , Paris,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-5180","authenticated-orcid":true,"given":"Stuart G.","family":"Tangye","sequence":"additional","affiliation":[{"name":"Clinical Immunogenomics Research Consortium Australasia (CIRCA) 11 , Darlinghurst,","place":["Australia"]},{"id":[{"id":"https:\/\/ror.org\/01b3dvp57","id-type":"ROR","asserted-by":"publisher"}],"name":"Garvan Institute of Medical Research 12 , Darlinghurst,","place":["Australia"]},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney 13 , Sydney,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-6304","authenticated-orcid":true,"given":"Alberto","family":"Pinzon-Charry","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t3p7e85","id-type":"ROR","asserted-by":"publisher"}],"name":"Queensland Paediatric Immunology & Allergy Service, Queensland Children\u2019s Hospital 1 , South Brisbane,","place":["Australia"]},{"name":"Clinical Immunogenomics Research Consortium Australasia (CIRCA) 11 , Darlinghurst,","place":["Australia"]},{"name":"Griffith University, Nathan Campus 14 , Nathan,","place":["Australia"]},{"name":"University of Queensland 15 , St Lucia,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"2025100909404808700_bib1","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/ng1297-399","article-title":"An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains","volume":"17","author":"Finnish-German APECED Consortium","year":"1997","journal-title":"Nat. Genet."},{"key":"2025100909404808700_bib2","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat. Genet."},{"key":"2025100909404808700_bib3","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.88782","article-title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"1","author":"Ferre","year":"2016","journal-title":"JCI Insight"},{"key":"2025100909404808700_bib4","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3389\/fimmu.2018.00098","article-title":"Twenty years of AIRE","volume":"9","author":"Perniola","year":"2018","journal-title":"Front. Immunol."},{"key":"2025100909404808700_bib5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210554","article-title":"Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1","volume":"218","author":"Bastard","year":"2021","journal-title":"J. Exp. Med."},{"key":"2025100909404808700_bib6","doi-asserted-by":"crossref","first-page":"723532","DOI":"10.3389\/fped.2021.723532","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"9","author":"Ferre","year":"2021","journal-title":"Front Pediatr."},{"key":"2025100909404808700_bib7","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1084\/jem.20091669","article-title":"Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines","volume":"207","author":"Kisand","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025100909404808700_bib8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1084\/jem.20091983","article-title":"Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I","volume":"207","author":"Puel","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025100909404808700_bib9","doi-asserted-by":"publisher","first-page":"631","DOI":"10.3390\/biomedicines8120631","article-title":"Novel pathogenic variants of the AIRE gene in two autoimmune polyendocrine syndrome type I cases with atypical presentation: Role of the NGS in diagnostic pathway and review of the literature","volume":"8","author":"Cinque","year":"2020","journal-title":"Biomedicines"},{"key":"2025100909404808700_bib10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.coi.2016.07.003","article-title":"AIRE-mutations and autoimmune disease","volume":"43","author":"Bruserud","year":"2016","journal-title":"Curr. Opin. Immunol."},{"key":"2025100909404808700_bib11","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1056\/NEJM199006283222601","article-title":"Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients","volume":"322","author":"Ahonen","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"2025100909404808700_bib12","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1136\/jmg.29.11.824","article-title":"Polyglandular autoimmune syndrome type I among Iranian Jews","volume":"29","author":"Zlotogora","year":"1992","journal-title":"J. Med. Genet."},{"key":"2025100909404808700_bib13","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1007\/s40618-020-01376-5","article-title":"Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: Case report and review of a series of 45 patients","volume":"44","author":"Fierabracci","year":"2021","journal-title":"J. Endocrinol. Invest."},{"key":"2025100909404808700_bib14","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1507\/endocrj.49.625","article-title":"A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: Case report and review of the literature in Japan","volume":"49","author":"Sato","year":"2002","journal-title":"Endocr. J."},{"key":"2025100909404808700_bib15","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000020000","article-title":"A case report and literature review: Identification of a novel AIRE gene mutation associated with Autoimmune Polyendocrine Syndrome Type 1 in East Asians","volume":"99","author":"Yan","year":"2020","journal-title":"Medicine"},{"key":"2025100909404808700_bib16","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/j.immuni.2015.04.021","article-title":"Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases","volume":"42","author":"Oftedal","year":"2015","journal-title":"Immunity"},{"key":"2025100909404808700_bib17","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.jaut.2017.10.010","article-title":"Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE)","volume":"88","author":"Abbott","year":"2018","journal-title":"J. Autoimmun."},{"key":"2025100909404808700_bib18","doi-asserted-by":"publisher","first-page":"106818","DOI":"10.1016\/j.isci.2023.106818","article-title":"Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes","volume":"26","author":"Oftedal","year":"2023","journal-title":"iScience"},{"key":"2025100909404808700_bib19","doi-asserted-by":"publisher","first-page":"4747","DOI":"10.1210\/jcem.86.10.7884","article-title":"A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis","volume":"86","author":"Cetani","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2025100909404808700_bib20","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s40618-022-01937-w","article-title":"A non-classical presentation of APECED in a family with heterozygous R203X AIRE gene mutation","volume":"46","author":"Radetti","year":"2023","journal-title":"J. Endocrinol. Invest."},{"key":"2025100909404808700_bib21","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2025100909404808700_bib22","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13072-020-0328-z","article-title":"Characterization of the plant homeodomain (PHD) reader family for their histone tail interactions","volume":"13","author":"Jain","year":"2020","journal-title":"Epigenetics Chromatin"},{"key":"2025100909404808700_bib23","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1038\/sj.embor.2008.11","article-title":"The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression","volume":"9","author":"Org","year":"2008","journal-title":"EMBO Rep."},{"key":"2025100909404808700_bib24","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s10875-024-01757-y","article-title":"Autoantibodies neutralizing GM-CSF in HIV-negative Colombian patients infected with cryptococcus gattii and C. Neoformans","volume":"44","author":"Arango-Franco","year":"2024","journal-title":"J. Clin. Immunol."},{"key":"2025100909404808700_bib25","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl4340","article-title":"Autoantibodies neutralizing type I IFNs are present in \u223c4% of uninfected individuals over 70 years old and account for \u223c20% of COVID-19 deaths","volume":"6","author":"Bastard","year":"2021","journal-title":"Sci. Immunol."},{"key":"2025100909404808700_bib26","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1016\/j.jaip.2023.04.015","article-title":"The Th17\/IL-17 Axis and host defense against fungal infections","volume":"11","author":"Tangye","year":"2023","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"2025100909404808700_bib27","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.3389\/fimmu.2017.01074","article-title":"Altered immune activation and IL-23 signaling in response to Candida albicans in autoimmune polyendocrine syndrome type 1","volume":"8","author":"Bruserud","year":"2017","journal-title":"Front. Immunol."},{"key":"2025100909404808700_bib28","doi-asserted-by":"publisher","first-page":"102917","DOI":"10.1016\/j.jaut.2022.102917","article-title":"Screening patients with autoimmune endocrine disorders for cytokine autoantibodies reveals monogenic immune deficiencies","volume":"133","author":"Sj\u00f8gren","year":"2022","journal-title":"J. Autoimmun."},{"key":"2025100909404808700_bib29","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1056\/NEJMoa2312665","article-title":"The role of interferon-\u03b3 in autoimmune polyendocrine syndrome type 1","volume":"390","author":"Oikonomou","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"2025100909404808700_bib30","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e28037","article-title":"Novel homozygous mutations in AIRE leading to APS-1 and potential mechanisms based on bioinformatics analysis","volume":"10","author":"Wu","year":"2024","journal-title":"Heliyon"},{"key":"2025100909404808700_bib31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201076","article-title":"Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation","volume":"218","author":"Goldfarb","year":"2021","journal-title":"J. Exp. Med."},{"key":"2025100909404808700_bib32","doi-asserted-by":"publisher","first-page":"15878","DOI":"10.1073\/pnas.0808470105","article-title":"Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity","volume":"105","author":"Koh","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025100909404808700_bib33","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1073\/pnas.1222023110","article-title":"Aire\u2019s plant homeodomain(PHD)-2 is critical for induction of immunological tolerance","volume":"110","author":"Yang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025100909404808700_bib34","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1128\/MCB.06359-11","article-title":"Unmodified histone H3K4 and DNA-dependent protein kinase recruit autoimmune regulator to target genes","volume":"32","author":"Zumer","year":"2012","journal-title":"Mol. Cell Biol"},{"key":"2025100909404808700_bib35","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/sj.embor.7400146","article-title":"Structures of protein domains that create or recognize histone modifications","volume":"5","author":"Bottomley","year":"2004","journal-title":"EMBO Rep."},{"key":"2025100909404808700_bib36","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of medical genetics and Genomics and the association for molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"2025100909404808700_bib37","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.cell.2009.12.030","article-title":"Aire's partners in the molecular control of immunological tolerance","volume":"140","author":"Abramson","year":"2010","journal-title":"Cell"},{"key":"2025100909404808700_bib38","doi-asserted-by":"publisher","first-page":"1572789","DOI":"10.3389\/fimmu.2025.1572789","article-title":"High-resolution transcriptional impact of AIRE: Effects of pathogenic variants p.Arg257Ter, p.Cys311Tyr, and polygenic risk variant p.Arg471Cys","volume":"16","author":"Berger","year":"2025","journal-title":"Front. Immunol."}],"container-title":["Journal of Human Immunity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jhi\/article-pdf\/doi\/10.70962\/jhi.20250151\/1951043\/jhi_20250151.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jhi\/article-pdf\/doi\/10.70962\/jhi.20250151\/1951043\/jhi_20250151.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:40:54Z","timestamp":1760017254000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jhi\/article\/1\/4\/e20250151\/278358\/A-novel-heterozygous-pathogenic-AIRE-variant"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,11,3]]}},"URL":"https:\/\/doi.org\/10.70962\/jhi.20250151","relation":{},"ISSN":["3065-8993"],"issn-type":[{"value":"3065-8993","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"article-number":"e20250151"}}