{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:07:40Z","timestamp":1791400060967,"version":"4.3.3"},"reference-count":28,"publisher":"BMJ","issue":"1","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2016,4,12]]},"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Although Beh\u00e7et's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed. Whole-exome sequencing was performed on genomic DNA, and cytokine production was determined from stimulated mononuclear cells. Inflammatory cytokine secretion and Nod2-mediated NF-\u03baB activation were analysed using the transfected cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>By whole-exome sequencing, we identified a common heterozygous missense mutation in <jats:italic>A20\/TNFAIP3<\/jats:italic>, a gene known to regulate NF-\u03baB signalling, for which all affected family members carried a heterozygous C243Y mutation in the ovarian tumour domain. Mononuclear cells obtained from the proband and his mother produced large amounts of interleukin 1\u03b2, IL-6 and tumour necrosis factor \u03b1 (TNF-a) on stimulation as compared with those from normal controls. Although inflammatory cytokine secretion was suppressed by wild-type transfected cells, it was suppressed to a much lesser extent by mutated C243Y <jats:italic>A20\/TNFAIP3<\/jats:italic>-transfected cells. In addition, impaired suppression of Nod2-mediated NF-\u03baB activation by C243Y <jats:italic>A20\/TNFAIP3<\/jats:italic> was observed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A C243Y mutation in <jats:italic>A20\/TNFAIP3<\/jats:italic> was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-\u03baB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2015-000223","type":"journal-article","created":{"date-parts":[[2016,12,10]],"date-time":"2016-12-10T01:24:21Z","timestamp":1481333061000},"page":"e000223","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":92,"title":["Novel heterozygous C243Y A20\/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Beh\u00e7et's disease"],"prefix":"10.1136","volume":"2","author":[{"given":"Tomonari","family":"Shigemura","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoe","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimoto","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Nakano","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Masumoto","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Ehime, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunaga","family":"Agematsu","sequence":"additional","affiliation":[{"name":"Department of Infection and Host Defense, Graduate School of Medicine, Shinshu University, Matsumoto, 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