Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

Bergithe E Oftedal, Alexander Hellesen, Martina M Erichsen, Eirik Bratland, Ayelet Vardi, Jaakko Perheentupa, E Helen Kemp, Torunn Fiskerstrand, Marte K Viken, Anthony P Weetman, Sarel J Fleishman, Siddharth Banka, William G Newman, W A C Sewell, Leila S Sozaeva, Tetyana Zayats, Kristoffer Haugarvoll, Elizaveta M Orlova, Jan Haavik, Stefan JohanssonPer M Knappskog, Kristian Løvås, Anette S B Wolff, Jakub Abramson, Eystein S Husebye

    Research output: Contribution to journalArticlepeer-review


    The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.
    Original languageEnglish
    Issue number6
    Publication statusPublished - 16 Jun 2015


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