@article{2437b07fd6434b37b3527969af489f2a,
title = "Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases",
abstract = "The autoimmune regulator (AIRE) gene is crucial forestablishing 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.",
author = "BE Oftedal and A Hellesen and MM Erichsen and E Bratland and Ayelet Vardi and J Perheentupa and EH Kemp and T Fiskerstrand and MK Viken and AP Weetman and SJ Fleishman and S Banka and WG Newman and WAC Sewell and LS Sozaeva and T Zayats and K Haugarvoll and EM Orlova and J Haavik and S Johansson and PM Knappskog and K Lovas and ASB Wolff and Jakub Abramson and ES Husebye",
note = "Regional Health Authorities of Western Norway; Norwegian Research Council; Novo Nordisk Foundation; Israel Science Foundation; Sy Syms Foundation; Bergen Medical Research Foundation; Nils Norman's Traveling Fund in Endocrinology; Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010] This study was supported by grants from The Regional Health Authorities of Western Norway, The Norwegian Research Council, Novo Nordisk Foundation, The Israel Science Foundation (J.A., S.J.F.), Sy Syms Foundation (J.A.), Bergen Medical Research Foundation (A.S.B.W.), and Nils Norman's Traveling Fund in Endocrinology (A.H.). B.E.O. and E.S.H. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Technical help from Hajirah Muneer, Elin Theodorsen, and Elisabeth Halvorsen is greatly acknowledged. We thank the patients and physicians of The National Registry of Organ-specific Autoimmune Diseases (Drs. Anne-Grethe Myhre, Johan Svartberg, Kristian Fougner, Anders Jorgensen, Tore Julsrud Berg, Kari Lima, Bjarne Mella, Bjorn Nedrebo, and Siri Carlsen) for collection of clinical information. We would like to thank Dr. Vinod Devalia, Princess of Wales Hospital, and Professor Mark Pritchard, University of Liverpool, for collecting pernicious anemia samples. Professor Christophe Benoist, Harvard Medical School, is thanked for generously providing human thymic 4D6 cells. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). B.E.O., A.H., A.S.B.W., E.B., and A.V. performed the experiments. M.K.V. did the HLA genotyping and S.J.F. did the in silico analysis and structural modeling. T.F. and P.M.K. provided the gen-analysis and microsatellite typing of the AIRE region and K.H., T.Z., and S.J. provided the genetic frequency data. M.M.E., J.P., E.H.K., A.P.W., S.B., W.G.N., W.A.C.S., L.S.S., E.M.O., K.L., and E.S.H. provided samples and clinical data for the patients. B.E.O., J.A., and E.S.H. planned and coordinated the study and wrote the manuscript. All authors discussed the results and commented on the manuscript.",
year = "2015",
month = jun,
day = "16",
doi = "10.1016/j.immuni.2015.04.021",
language = "English",
volume = "42",
pages = "1185--1196",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}