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- PMID: 26084028
- UKPMCID: 26084028
- DOI: 10.1016/j.immuni.2015.04.021
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Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.
Oftedal, Bergithe E; Hellesen, Alexander; Erichsen, Martina M; Bratland, Eirik; Vardi, Ayelet; Perheentupa, Jaakko; Kemp, E Helen; Fiskerstrand, Torunn; Viken, Marte K; Weetman, Anthony P; Fleishman, Sarel J; Banka, Siddharth; Newman, William G; Sewell, W A C; Sozaeva, Leila S; Zayats, Tetyana; Haugarvoll, Kristoffer; Orlova, Elizaveta M; Haavik, Jan; Johansson, Stefan; Knappskog, Per M; Løvås, Kristian; Wolff, Anette S B; Abramson, Jakub; Husebye, Eystein S
Immunity. 2015;42(6):1185-96.
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Full-text held externally
- PMID: 26084028
- UKPMCID: 26084028
- DOI: 10.1016/j.immuni.2015.04.021
Abstract
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.
Bibliographic metadata
- Oftedal, Bergithe E
- Hellesen, Alexander
- Erichsen, Martina M
- Bratland, Eirik
- Vardi, Ayelet
- Perheentupa, Jaakko
- Kemp, E Helen
- Fiskerstrand, Torunn
- Viken, Marte K
- Weetman, Anthony P
- Fleishman, Sarel J
- Banka, Siddharth
- Newman, William G
- Sewell, W A C
- Sozaeva, Leila S
- Zayats, Tetyana
- Haugarvoll, Kristoffer
- Orlova, Elizaveta M
- Haavik, Jan
- Johansson, Stefan
- Knappskog, Per M
- Løvås, Kristian
- Wolff, Anette S B
- Abramson, Jakub
- Husebye, Eystein S