title: Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.
abstract: Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Daniella M
authors.identifier: 0000-0002-1660-8438
authors.initials: DM
authors.lastname: Schwartz
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Stoffels
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Park
authors.affiliation: Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: FMF Arthritis Vasculitis and Orphan Disease Research Center (FAVOR), Gulhane Military Medical Academy, Ankara, Turkey.
authors.forename: Erkan
authors.initials: E
authors.lastname: Demirkaya
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takeuchi
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Wanxia Li
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Celeste
authors.initials: C
authors.lastname: Chen
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Chin
authors.affiliation: Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Kristien
authors.initials: K
authors.lastname: Zaal
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.affiliation: Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hanson
authors.affiliation: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yu
authors.affiliation: National Institute of Health Intramural Sequencing Center, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Systemic Autoimmune Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Sarfaraz A
authors.initials: SA
authors.lastname: Hasni
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., San Francisco, California, USA.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Wertz
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Ombrello
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Stone
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Jones
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Beverly K
authors.initials: BK
authors.lastname: Barham
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Leavis
authors.affiliation: Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Annet
authors.initials: A
authors.lastname: van Royen-Kerkof
authors.affiliation: Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Cailin
authors.initials: C
authors.lastname: Sibley
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
authors.forename: Ezgi D
authors.initials: ED
authors.lastname: Batu
authors.affiliation: Department of Internal Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.affiliation: Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.affiliation: Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
authors.forename: Seza
authors.initials: S
authors.lastname: Ozen
authors.affiliation: Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: JaeJin
authors.initials: J
authors.lastname: Chae
authors.affiliation: Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
mesh_terms: D017668:Age of Onset; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: C119724:AGFG1 protein, human; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C491731:IKBKG protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D048029:TNF Receptor-Associated Factor 6; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3