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: [email protected].
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.