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

Immunity. 2015 Jun 16;42(6):1185-96. doi: 10.1016/j.immuni.2015.04.021.

Bergithe E Oftedal ¹, Alexander Hellesen ², Martina M Erichsen ³, Eirik Bratland ¹, Ayelet Vardi ⁴, Jaakko Perheentupa ⁵, E Helen Kemp ⁶, Torunn Fiskerstrand ⁷, Marte K Viken ⁸, Anthony P Weetman ⁶, Sarel J Fleishman ⁹, Siddharth Banka ¹⁰, William G Newman ¹⁰, W A C Sewell ¹¹, Leila S Sozaeva ¹², Tetyana Zayats ¹³, Kristoffer Haugarvoll ¹⁴, Elizaveta M Orlova ¹², Jan Haavik ¹³, Stefan Johansson ⁷, Per M Knappskog ⁷, Kristian Løvås ², Anette S B Wolff ¹, Jakub Abramson ⁴, Eystein S Husebye ¹⁵

Affiliations

1 Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
2 Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
3 Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
4 Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
5 Hospital for Children and Adolescents, University of Helsinki, 00100 Helsinki, Finland.
6 Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK.
7 Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
8 Department of Immunology, Oslo University Hospital and University of Oslo, 0316 Oslo, Norway.
9 Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
10 Manchester Centre for Genomic Medicine, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK.
11 Path Links Immunology, Scunthorpe General Hospital, Scunthorpe DN15 7BH, UK.
12 Endocrinological Research Center, Institute of Pediatric Endocrinology, Moscow 117036, Russian Federation.
13 K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.
14 Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.
15 Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: eystein.husebye@k2.uib.no.

PMID: 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.

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