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

• DOI: 10.1016/j.immuni.2015.04.021
• Publication Date: 2015-06-16T15:45:31Z
• Authors: 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 Haugar...; Elizaveta M. Orlova; Jan Haavik; Stefan Johansson; Per M. Knappskog; Kristian Løvås; Anette S.B. Wolff; Jakub Abramson; Eystein S. Husebye
• Keywords: Autoimmune regulator; Penetrance

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.