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

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity

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Oftedal, BE; Hellesen, A; Erichsen, MM; Bratland, E; Vardi, A; Perheentupa, J; Kemp, EH; Fiskerstrand, T; Viken, MK; Weetman, AP; Fleishman, SJ; Banka, S; Newman, WG; Sewell, WAC; Sozaeva, LS; Zayats, T; Haugarvoll, K; Orlova, EM; Haavik, J; Johansson, S; Knappskog, PM; Lovas, K; Wolff, ASB; Abramson, J; Husebye, ES

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.

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