title: Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease.
abstract: OBJECTIVE
  Although Behçet'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.
  
  
  METHODS
  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-κB activation were analysed using the transfected cells.
  
  
  RESULTS
  By whole-exome sequencing, we identified a common heterozygous missense mutation in A20/TNFAIP3, a gene known to regulate NF-κB 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 1β, IL-6 and tumour necrosis factor α (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 A20/TNFAIP3-transfected cells. In addition, impaired suppression of Nod2-mediated NF-κB activation by C243Y A20/TNFAIP3 was observed.
  
  
  CONCLUSIONS
  A C243Y mutation in A20/TNFAIP3 was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family.
authors.affiliation: Department of Pediatrics , Shinshu University School of Medicine , Matsumoto , Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Shigemura
authors.affiliation: Department of Pathology , Ehime University Proteo-Science Center and Graduate School of Medicine , Ehime , Japan.
authors.forename: Naoe
authors.initials: N
authors.lastname: Kaneko
authors.affiliation: Department of Pediatrics , Shinshu University School of Medicine , Matsumoto , Japan.
authors.forename: Norimoto
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Infection and Host Defense , Graduate School of Medicine, Shinshu University , Matsumoto , Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics , Shinshu University School of Medicine , Matsumoto , Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Department of Pathology , Ehime University Proteo-Science Center and Graduate School of Medicine , Ehime , Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Department of Pathology , Ehime University Proteo-Science Center and Graduate School of Medicine , Ehime , Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.affiliation: Department of Infection and Host Defense , Graduate School of Medicine, Shinshu University , Matsumoto , Japan.
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
keywords: Behcet's disease; Cytokines; Fever Syndromes; Inflammation