title: Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.
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.
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Bergithe E
authors.initials: BE
authors.lastname: Oftedal
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hellesen
authors.affiliation: Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Martina M
authors.initials: MM
authors.lastname: Erichsen
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Eirik
authors.initials: E
authors.lastname: Bratland
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Vardi
authors.affiliation: Hospital for Children and Adolescents, University of Helsinki, 00100 Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.affiliation: Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: E Helen
authors.initials: EH
authors.lastname: Kemp
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Torunn
authors.initials: T
authors.lastname: Fiskerstrand
authors.affiliation: Department of Immunology, Oslo University Hospital and University of Oslo, 0316 Oslo, Norway.
authors.forename: Marte K
authors.initials: MK
authors.lastname: Viken
authors.affiliation: Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Weetman
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Sarel J
authors.initials: SJ
authors.lastname: Fleishman
authors.affiliation: 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.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Path Links Immunology, Scunthorpe General Hospital, Scunthorpe DN15 7BH, UK.
authors.forename: W A C
authors.initials: WA
authors.lastname: Sewell
authors.affiliation: Endocrinological Research Center, Institute of Pediatric Endocrinology, Moscow 117036, Russian Federation.
authors.forename: Leila S
authors.initials: LS
authors.lastname: Sozaeva
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Zayats
authors.affiliation: Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Haugarvoll
authors.affiliation: Endocrinological Research Center, Institute of Pediatric Endocrinology, Moscow 117036, Russian Federation.
authors.forename: Elizaveta M
authors.initials: EM
authors.lastname: Orlova
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Løvås
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Anette S B
authors.initials: AS
authors.lastname: Wolff
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Jakub
authors.initials: J
authors.lastname: Abramson
authors.affiliation: 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.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009664:Norway; D009928:Organ Specificity / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D012426:Russia; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D014157:Transcription Factors; D000096927:AIRE Protein