title: Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome.
abstract: BACKGROUND
  Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype.
  
  
  OBJECTIVE
  The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype.
  
  
  METHODS
  Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways.
  
  
  RESULTS
  A de novo heterozygous frameshift mutation of TNF-α-induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20).
  
  
  CONCLUSIONS
  Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: m.takagi.ped@tmd.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Pediatrics, Kitasato University, Kanagawa, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Ogata
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ueno
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tzuwen
authors.initials: T
authors.lastname: Yeh
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Motoy
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Nanya
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Transfusion Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kajiwara
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Department of Pediatrics, Nagoya University, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Department of Pediatrics, Nagoya University, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, Kitasato University Medical Center, Saitama, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bando
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Gunma Children's Medical Center, Gunma, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Nagoya University, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
mesh_terms: D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D010641:Phenotype; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics* / Q000276:immunology
chemical_list: D016328:NF-kappa B; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: Autoimmune lymphoproliferative syndrome; TNFAIP3 (A20)