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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-06, Vol.42 (6), p.1185-1196
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; AIRE Protein; Amino Acid Sequence; Autoimmune diseases; Autoimmunity - genetics; Baldness; Child; Child, Preschool; Disease; DNA Mutational Analysis - methods; Enamel; Female; Gene Frequency; Genes, Dominant - genetics; Genomes; Humans; Immunology; Lymphocytes; Male; Microsatellite Repeats - genetics; Molecular Sequence Data; Mutation; Mutation - genetics; Norway; Organ Specificity - genetics; Patients; Pedigree; Penetrance; Phenotype; Polyendocrinopathies, Autoimmune - genetics; Proteins; Russia; Transcription Factors - genetics; Young Adult
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.04.021

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.