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

Autor:	Oftedal BE; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Hellesen A; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Erichsen MM; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Bratland E; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Vardi A; Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel., Perheentupa J; Hospital for Children and Adolescents, University of Helsinki, 00100 Helsinki, Finland., Kemp EH; Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK., Fiskerstrand T; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Viken MK; Department of Immunology, Oslo University Hospital and University of Oslo, 0316 Oslo, Norway., Weetman AP; Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield S10 2RX, UK., Fleishman SJ; Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel., Banka S; 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., Newman WG; 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., Sewell WA; Path Links Immunology, Scunthorpe General Hospital, Scunthorpe DN15 7BH, UK., Sozaeva LS; Endocrinological Research Center, Institute of Pediatric Endocrinology, Moscow 117036, Russian Federation., Zayats T; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway., Haugarvoll K; Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway., Orlova EM; Endocrinological Research Center, Institute of Pediatric Endocrinology, Moscow 117036, Russian Federation., Haavik J; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, 5021 Bergen, Norway., Johansson S; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Knappskog PM; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Løvås K; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway., Wolff AS; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway., Abramson J; Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel., Husebye ES; 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.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2015 Jun 16; Vol. 42 (6), pp. 1185-96.
DOI:	10.1016/j.immuni.2015.04.021
Abstrakt:	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. (Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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