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

2015; Cell Press; Volume: 42; Issue: 6 Linguagem: Inglês

10.1016/j.immuni.2015.04.021

1097-4180

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, William A. Sewell, Leila Sozaeva, Tetyana Zayats, Kristoffer Haugarvoll, Elizaveta Orlova, Jan Haavik, Stefan Johansson, Per M. Knappskog, Kristian Løvås, Anette S. B. Wolff, Jakub Abramson, Eystein S. Husebye,

Diabetes and associated disorders

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.