Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Immunity (Cambridge, Mass.), 2015-06, Vol.42 (6), p.1185-1196

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Heterozygous mutations in AIRE cause organ-specific autoimmune disease•Mono-allelic mutations with dominant effects cluster within the PHD1 domain of AIRE•These mutations suppress wild-type AIRE in a dominant-negative manner•Relatively high frequencies of these mutations are found in the population This paper by Husebye and colleagues directly links heterozygous mutations in the autoimmune regulator (AIRE) gene to organ-specific autoimmunity, including APS-1. The authors show that these mutations cluster within the first PHD domain of AIRE and exert a dominant-negative effect on wild-type AIRE in vitro.