{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:09:07Z","timestamp":1791587347311,"version":"4.3.4"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T00:00:00Z","timestamp":1673136000000},"content-version":"vor","delay-in-days":229,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate &amp;gt;300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and &amp;gt;45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1530\/eje-21-0730","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T10:38:57Z","timestamp":1651833537000},"page":"111-122","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":16,"title":["Spectrum of germline <i>AIRE<\/i> mutations causing APS-1 and familial hypoparathyroidism"],"prefix":"10.1093","volume":"187","author":[{"given":"Treena","family":"Cranston","sequence":"first","affiliation":[{"name":"Oxford Genetics Laboratories, Churchill Hospital , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Boon","sequence":"additional","affiliation":[{"name":"Oxford Genetics Laboratories, Churchill Hospital , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mie K","family":"Olesen","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona J","family":"Ryan","sequence":"additional","affiliation":[{"name":"Paediatric Endocrinology, Children's Hospital, John Radcliffe Hospital , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Shears","sequence":"additional","affiliation":[{"name":"Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"London","sequence":"additional","affiliation":[{"name":"Paediatric Endocrinology, Children's Hospital, John Radcliffe Hospital , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussam","family":"Rostom","sequence":"additional","affiliation":[{"name":"Nuffield Department of Women's and Reproductive Health, University of Oxford , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taha","family":"Elajnaf","sequence":"additional","affiliation":[{"name":"Nuffield Department of Women's and Reproductive Health, University of Oxford , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh V","family":"Thakker","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford , Oxford, UK"},{"name":"National Institute for Health Research Oxford Biomedical Research Centre , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-5170","authenticated-orcid":false,"given":"Fadil M","family":"Hannan","sequence":"additional","affiliation":[{"name":"Nuffield Department of Women's and Reproductive Health, University of Oxford , Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"2023010809165930700_bib1","doi-asserted-by":"crossref","first-page":"e88782","DOI":"10.1172\/jci.insight.88782","article-title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"1","author":"Ferre","year":"2016","journal-title":"JCI Insight"},{"key":"2023010809165930700_bib2","doi-asserted-by":"crossref","first-page":"17055","DOI":"10.1038\/nrdp.2017.55","article-title":"Hypoparathyroidism","volume":"3","author":"Mannstadt","year":"2017","journal-title":"Nature Reviews Disease Primers"},{"key":"2023010809165930700_bib3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.coi.2016.07.003","article-title":"AIRE-mutations and autoimmune disease","volume":"43","author":"Bruserud","year":"2016","journal-title":"Current Opinion in Immunology"},{"key":"2023010809165930700_bib4","doi-asserted-by":"crossref","first-page":"eaav5597","DOI":"10.1126\/scitranslmed.aav5597","article-title":"Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance","volume":"11","author":"Ferre","year":"2019","journal-title":"Science Translational Medicine"},{"key":"2023010809165930700_bib5","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1210\/jc.2005-2611","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"91","author":"Perheentupa","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809165930700_bib6","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune polyendocrine syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"New England Journal of Medicine"},{"key":"2023010809165930700_bib7","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.coi.2017.10.003","article-title":"Insights into immune tolerance from AIRE deficiency","volume":"49","author":"Proekt","year":"2017","journal-title":"Current Opinion in Immunology"},{"key":"2023010809165930700_bib8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/ni.3675","article-title":"The transcriptional regulator Aire binds to and activates super-enhancers","volume":"18","author":"Bansal","year":"2017","journal-title":"Nature Immunology"},{"key":"2023010809165930700_bib9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00439-017-1779-6","article-title":"The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies","volume":"136","author":"Stenson","year":"2017","journal-title":"Human Genetics"},{"key":"2023010809165930700_bib10","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1038\/s41467-020-15448-w","article-title":"Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance","volume":"11","author":"Huoh","year":"2020","journal-title":"Nature Communications"},{"key":"2023010809165930700_bib11","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.immuni.2015.04.021","article-title":"Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases","volume":"42","author":"Oftedal","year":"2015","journal-title":"Immunity"},{"key":"2023010809165930700_bib12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/humu.1176","article-title":"APECED mutations in the autoimmune regulator (AIRE) gene","volume":"18","author":"Heino","year":"2001","journal-title":"Human Mutation"},{"key":"2023010809165930700_bib13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nature Genetics"},{"key":"2023010809165930700_bib14","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1086\/302145","article-title":"A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1","volume":"63","author":"Pearce","year":"1998","journal-title":"American Journal of Human Genetics"},{"key":"2023010809165930700_bib15","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1210\/clinem\/dgaa111","article-title":"Neonatal hypocalcemic seizures in offspring of a mother with familial hypocalciuric hypercalcemia type 1 (FHH1)","volume":"105","author":"Dharmaraj","year":"2020","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809165930700_bib16","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2023010809165930700_bib17","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gkx439","article-title":"SDM: a server for predicting effects of mutations on protein stability","volume":"45","author":"Pandurangan","year":"2017","journal-title":"Nucleic Acids Research"},{"key":"2023010809165930700_bib18","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.it.2020.04.007","article-title":"The speckled protein (SP) family: immunity's chromatin readers","volume":"41","author":"Fraschilla","year":"2020","journal-title":"Trends in Immunology"},{"key":"2023010809165930700_bib19","doi-asserted-by":"crossref","first-page":"15878","DOI":"10.1073\/pnas.0808470105","article-title":"Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity","volume":"105","author":"Koh","year":"2008","journal-title":"PNAS"},{"key":"2023010809165930700_bib20","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1074\/jbc.M707211200","article-title":"AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity","volume":"283","author":"Ferguson","year":"2008","journal-title":"Journal of Biological Chemistry"},{"key":"2023010809165930700_bib21","doi-asserted-by":"crossref","first-page":"eaav6778","DOI":"10.1126\/sciimmunol.aav6778","article-title":"AIRE expression controls the peripheral selection of autoreactive B cells","volume":"4","author":"Sng","year":"2019","journal-title":"Science Immunology"},{"key":"2023010809165930700_bib22","first-page":"P276","article-title":"Autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: a case report","volume":"89","author":"Celik","year":"2018","journal-title":"ESPE Abstracts"},{"key":"2023010809165930700_bib23","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1210\/jc.2016-3836","article-title":"Exome sequencing reveals mutations in AIRE as a cause of isolated hypoparathyroidism","volume":"102","author":"Li","year":"2017","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809165930700_bib24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.sbi.2012.02.006","article-title":"Helical assembly in the death domain (DD) superfamily","volume":"22","author":"Ferrao","year":"2012","journal-title":"Current Opinion in Structural Biology"},{"key":"2023010809165930700_bib25","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.ajhg.2019.09.016","article-title":"Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population","volume":"105","author":"Nakka","year":"2019","journal-title":"American Journal of Human Genetics"},{"key":"2023010809165930700_bib26"},{"key":"2023010809165930700_bib27","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1093\/humrep\/13.2.313","article-title":"Origin and mechanisms of non-disjunction in human autosomal trisomies","volume":"13","author":"Nicolaidis","year":"1998","journal-title":"Human Reproduction"},{"key":"2023010809165930700_bib28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1297\/cpe.27.113","article-title":"Uniparental disomy as a cause of pediatric endocrine disorders","volume":"27","author":"Matsubara","year":"2018","journal-title":"Clinical Pediatric Endocrinology"},{"key":"2023010809165930700_bib29","first-page":"1074","article-title":"Normal phenotype with paternal uniparental isodisomy for chromosome 21","volume":"53","author":"Blouin","year":"1993","journal-title":"American Journal of Human Genetics"},{"key":"2023010809165930700_bib30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1159\/000488572","article-title":"Classification of uniparental isodisomy patterns that cause autosomal recessive disorders: proposed mechanisms of different proportions and parental origin in each pattern","volume":"154","author":"Niida","year":"2018","journal-title":"Cytogenetic and Genome Research"},{"key":"2023010809165930700_bib31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/00125817-200105000-00011","article-title":"American College of Medical Genetics statement of diagnostic testing for uniparental disomy","volume":"3","author":"Shaffer","year":"2001","journal-title":"Genetics in Medicine"},{"key":"2023010809165930700_bib32","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/j.1742-4658.2005.05065.x","article-title":"The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin alpha molecules","volume":"273","author":"Ilmarinen","year":"2006","journal-title":"FEBS Journal"},{"key":"2023010809165930700_bib33","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1073\/pnas.1222023110","article-title":"Aire's plant homeodomain(PHD)-2 is critical for induction of immunological tolerance","volume":"110","author":"Yang","year":"2013","journal-title":"PNAS"}],"container-title":["European Journal of Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/eje.bioscientifica.com\/view\/journals\/eje\/187\/1\/EJE-21-0730.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/187\/1\/111\/48516259\/eje-21-0730.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/187\/1\/111\/48516259\/eje-21-0730.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T16:17:05Z","timestamp":1676391425000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/187\/1\/111\/6972130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,7,1]]}},"URL":"https:\/\/doi.org\/10.1530\/eje-21-0730","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,7]]},"published":{"date-parts":[[2022,5,24]]}}}