A novel heterozygous pathogenic <i>AIRE</i> variant causing autoimmunity but not infectious susceptibility
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is characterized by the triad of hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis due to biallelic deleterious variants in <i>AIRE</i>. 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 <i>AIRE</i> variant, c.1010G>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 AIRE<sup>C337F</sup> 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 <i>AIRE</i> variants, AIRE<sup>C337F</sup> localizes to the highly conserved PHD1 domain. Thus, our findings identify a novel pathogenic heterozygous <i>AIRE</i> 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.
Authors
- Alberto Pinzón‐Charry (ORCID: https://orcid.org/0000-0001-8870-6304)
- Bergithe E Oftedal (ORCID: https://orcid.org/0000-0003-4248-7737)
- Syndia Lazarus (ORCID: https://orcid.org/0000-0002-5221-7303)
- Christopher M. Richmond (ORCID: https://orcid.org/0000-0002-9778-4344)
- Jean‐Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
- Mélanie Migaud (ORCID: https://orcid.org/0000-0003-3062-1214)
- Anne Puel (ORCID: https://orcid.org/0000-0003-2603-0323)
- Stuart G. Tangye (ORCID: https://orcid.org/0000-0002-5360-5180)
- Dorsa Iraji
- Anna Sullivan
- Mounavi Vemula
Institutions
- Griffith University (AU)
- The University of Sydney (AU)
- Howard Hughes Medical Institute (US)
- Garvan Institute of Medical Research (AU)
- Inserm (FR)
- The University of Queensland (AU)
- Université Paris Cité (FR)
- Royal Brisbane and Women's Hospital (AU)
- Hospital for Sick Children (CA)
- UNSW Sydney (AU)
- Hospital for Sick Children Pediatric Center (US)
- Ecogenomics (Japan) (JP)
- Uni Research (Norway) (NO)
- Clinical Research Consortium (US)
- Human Genetic of Infectious Diseases (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Children's Health Queensland Hospital and Health Service (AU)
- University of Bergen (NO)
- Rockefeller University (US)
Publication Details
- Journal
- Journal of Human Immunity
- Published
- 2025-10-09
- DOI
- https://doi.org/10.70962/jhi.20250151
- Primary Topic
- Adrenal Hormones and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- St. Giles Foundation
- Genomic Health
- Fondation du Souffle
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- Georgia Clinical and Translational Science Alliance
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation pour la Recherche Médicale
- Stavros Niarchos Foundation
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- National Center for Advancing Translational Sciences