{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T01:40:05Z","timestamp":1783561205906,"version":"3.55.0"},"reference-count":20,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,5,15]],"date-time":"2022-05-15T00:00:00Z","timestamp":1652572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Achalasia\u2010addisonianism\u2010alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (<jats:italic>AAAS<\/jats:italic>). Aladin is a member of the WD\u2010repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in <jats:italic>AAAS<\/jats:italic> presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow\u2010up testing in the proband's affected sister revealed that she also inherited the biallelic <jats:italic>AAAS<\/jats:italic> variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1966","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T06:30:29Z","timestamp":1652682629000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Functional validation of a novel <i>AAAS<\/i> variant in an atypical presentation of Allgrove syndrome"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-506X","authenticated-orcid":false,"given":"Erica L.","family":"Macke","sequence":"first","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-2211","authenticated-orcid":false,"given":"Joel A.","family":"Morales\u2010Rosado","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K.","family":"Macklin\u2010Mantia","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher T.","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Oskarsson","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric W.","family":"Klee","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Clinical Genomics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-3881","authenticated-orcid":false,"given":"Klaas J.","family":"Wierenga","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(78)91268\u20100"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/S13073\u2010019\u20100690\u20102"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/PNAS.1031047100"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000020474"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.58.6.962"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/HMG\/10.3.283"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awf270"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2018.12.015"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/JNNP.74.5.654"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1139\/O05\u2010198"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00431\u2010017\u20103068\u20108"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431\u2010010\u20101222\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rgmx.2020.09.003"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201017\u20100642"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/JCEM.86.11.8037"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM\u20102018\u20100023"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968\u20100004(99)01384\u20105"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/81642"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1966","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1966","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1966","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T12:10:03Z","timestamp":1692879003000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1966"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,15]]},"references-count":20,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1002\/mgg3.1966"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1966","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,15]]},"assertion":[{"value":"2021-10-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1966"}}