{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:17:29Z","timestamp":1790727449167,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["15\/CDA\/3490"],"award-info":[{"award-number":["15\/CDA\/3490"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014364","name":"National Children's Research Centre","doi-asserted-by":"publisher","award":["C\/18\/6"],"award-info":[{"award-number":["C\/18\/6"]}],"id":[{"id":"10.13039\/100014364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["779295"],"award-info":[{"award-number":["779295"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Monogenic Beh\u00e7et\u2019s disease (BD)\u2013like conditions are increasingly recognized and to date have been found to predominantly involve loss\u2010of\u2010function variants in <jats:italic>TNFAIP3.<\/jats:italic> This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD\u2010like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v\u2010rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA<jats:sup>\u2212\/\u2212<\/jats:sup> mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF\u2010\u03baB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild\u2010type and truncated RELA in experimental systems and patient samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA<jats:sup>\u2212\/\u2212<\/jats:sup> mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild\u2010type RELA; however, there was no difference in RELA nuclear translocation. In RelA<jats:sup>\u2212\/\u2212<\/jats:sup> MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98\u2010fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild\u2010type RELA (<jats:italic>P<\/jats:italic> = 0.036).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data indicate that <jats:italic>RELA<\/jats:italic> loss\u2010of\u2010function mutations cause BD\u2010like autoinflammation and NMO via impaired NF\u2010\u03baB signaling and increased apoptosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41531","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T04:04:33Z","timestamp":1600920273000},"page":"490-497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A Novel <i>RELA<\/i> Truncating Mutation in a Familial Beh\u00e7et\u2019s Disease\u2013like Mucocutaneous Ulcerative Condition"],"prefix":"10.1002","volume":"73","author":[{"given":"Fahd","family":"Adeeb","sequence":"first","affiliation":[{"name":"University Hospital Limerick  Limerick Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2014-934X","authenticated-orcid":false,"given":"Emma R.","family":"Dorris","sequence":"additional","affiliation":[{"name":"University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh E.","family":"Morgan","sequence":"additional","affiliation":[{"name":"University College Dublin National Children\u2019s Research Centre, and Our Lady\u2019s Children\u2019s Hospital Crumlin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Lawless","sequence":"additional","affiliation":[{"name":"NIHR Leeds Institute of Rheumatic and Musculoskeletal Medicine and St James\u2019s University Hospital  Leeds 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Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7910-0554","authenticated-orcid":false,"given":"Sinisa","family":"Savic","sequence":"additional","affiliation":[{"name":"NIHR Leeds Institute of Rheumatic and Musculoskeletal Medicine and St James\u2019s University Hospital  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-3926","authenticated-orcid":false,"given":"Anthony G.","family":"Wilson","sequence":"additional","affiliation":[{"name":"University College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Fraser","sequence":"additional","affiliation":[{"name":"University Hospital Limerick and University of Limerick School of Medicine  Limerick 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