ArticleNature genetics2016
Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.
Open access · greenAbstract readMulticenter Study
In one paragraph
Article in Nature genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 347 papers, 2 of them syntheses that pooled it.
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347citing papers in PubMed, 2 pooled it
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Who cites it
347 citing papers in PubMed, 2 syntheses or guidelines pooled it, 613 citations in OpenAlex.
- Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency.Clinical immunology (Orlando, Fla.) · 2024Pooled it
- Three Chinese pedigrees of A20 haploinsufficiency: clinical, cytokine and molecular characterization.Frontiers in immunology · 2022Pooled it
- The ubiquitin-editing enzyme A20 (TNFAIP3): mechanisms of activation, biological function, diseases and therapeutic targets.Molecular biomedicine · 2026Review
- Landscape of Somatic Mutations in a Large Cohort of Chinese Patients With Immune Dysregulations.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
- Genetic Variations inGenes · 2026Article
- Autosomal recessive A20 zinc finger 7 mutation is associated with early-onset lupus-like disease.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Limitations of EBV transformed human Raji B cells as a model for measuring canonical NF-κB activation.bioRxiv : the preprint server for biology · 2026Article
- Identification of genetic variants in B cell expressed genes associated with systemic lupus erythematosus in African American females.ImmunoHorizons · 2026Article
- How I Treat: Haploinsufficiency of A20.Journal of human immunity · 2026Review
- Reducing Unmet Needs in Hidradenitis Suppurativa by Including the Hair Follicle Among an Arsenal of Targets.Experimental dermatology · 2026Review
- Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review).Molecular medicine reports · 2026Review
- BIRC3 (Encoding cIAP2) Variants Result in Dysregulated RIPK1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease.Gastroenterology · 2026Article
- Behçet's spectrum disorders: genetic and immunological insights into an emerging disease concept.World journal of pediatrics : WJP · 2026Review
- Abnormal immunoglobulin expression and B-cell follicle organization in inborn errors of immunity/primary immunodeficiency.Virchows Archiv : an international journal of pathology · 2026Article
- Article
- Clinical Phenotypes and Genetic Findings in Very-Early-Onset Inflammatory Bowel Disease: A Vietnamese Pediatric Cohort Study.Children (Basel, Switzerland) · 2026Article
- Loop of N2-polarized neutrophils and exhausted CD8 + T cells induces immunotherapy resistance in NSCLC.Molecular and cellular biochemistry · 2026Article
- [Haploinsufficiency of A20 in a family caused by a heterozygous deletion in theZhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Article
- Antigen Microarray Reveals Broad and Subclinical Autoimmunity in Patients with Inborn Errors of Immunity.Journal of clinical immunology · 2026Article
- Pediatric Evans Syndrome as a Multisystem Immune Disorder: A 13-Year Longitudinal Experience from a Single Academic Center.Pediatric reports · 2026Article
287 more citing papers are in PubMed but not listed here.
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Authors and funding
41 authors at 11 institutions in 4 countries.
Qing ZhouInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Hongying WangInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Daniella M SchwartzMolecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.ORCID 0000-0002-1660-8438
Monique StoffelsInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Yong Hwan ParkInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Yuan ZhangGenetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
Dan YangLaboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Erkan DemirkayaFMF Arthritis Vasculitis and Orphan Disease Research Center (FAVOR), Gulhane Military Medical Academy, Ankara, Turkey.
Masaki TakeuchiInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Wanxia Li TsaiTranslational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Jonathan J LyonsGenetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
Xiaomin YuGenetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
Claudia OuyangAutoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Celeste ChenInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
David T ChinInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Kristien ZaalLight Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Settara C ChandrasekharappaCancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
Eric P HansonAutoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Zhen YuLaboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
James C MullikinNational Institute of Health Intramural Sequencing Center, National Human Genome Research Institute, Bethesda, Maryland, USA.
Sarfaraz A HasniSystemic Autoimmune Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Ingrid E WertzDepartment of Molecular Oncology, Genentech, Inc., San Francisco, California, USA.
Amanda K OmbrelloInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Deborah L StoneInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Patrycja HoffmannInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Anne JonesInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Beverly K BarhamInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Helen L LeavisDepartment of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Annet van Royen-KerkofDepartment of Pediatric Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
Cailin SibleyDivision of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, Oregon, USA.
Ezgi D BatuDepartment of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
Ahmet GülDepartment of Internal Medicine, Istanbul University, Istanbul, Turkey.
Richard M SiegelAutoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Manfred BoehmLaboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Joshua D MilnerGenetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
Seza OzenDepartment of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
Massimo GadinaTranslational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
JaeJin ChaeInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Ronald M LaxerDivision of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Daniel L KastnerInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
Ivona AksentijevichInflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
National Human Genome Research Institute · USNational Institute of Arthritis and Musculoskeletal and Skin Diseases · USNational Institute of Allergy and Infectious Diseases · USNational Heart Lung and Blood Institute · USHacettepe University · TRUniversity Medical Center Utrecht · NLIstanbul University · TRMolecular Oncology (United States) · USOregon Health & Science University · USTurkish Armed Forces · TRUniversity of Toronto · CA
Funding
Inter- and Intra-Species Comparative SequencingZIBHG000196 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI THOMAS, JAMES · 2009 to 2025
$177.6MClinical Support Services for the NIAMS Intramural Research ProgramZIDAR041180 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI COLBERT, ROBERT · 2009 to 2025
$119.2MTranslational Immunology research: a support for clinical immunological researchZICAR041181 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI GADINA, MASSIMO · 2009 to 2025
$31.5MClinical Training in RheumatologyZIEAR041176 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI COLBERT, ROBERT · 2009 to 2025
$29.8MVascular remodeling in patients with rare genetic disordersZIAHL006077 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI BOEHM, MANFRED · 2010 to 2025
$22.9MGenetics, Pathophysiology, and Treatment of Dominant Autoinflammatory DiseasesZIAHG200373 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI KASTNER, DANIEL · 2011 to 2024
$21.0MNIAMS Light Imaging FacilityZICAR041186 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI RANDAZZO, DAVIDE · 2010 to 2025
$18.2MComparative Genomics Unit ResearchZIAHG200330 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI MULLIKIN, JAMES C · 2009 to 2022
$17.9MNHGRI/DIR Genomics CoreZICHG200346 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI CHANDRASEKHARAPPA, SETTARA · 2010 to 2025
$14.5MPOSITIONAL CLONING OF THE MEN1 GENEZIAHG000029 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI CHANDRASEKHARAPPA, SETTARA · 2009 to 2025
$13.3MGenetics, Natural History, and Pathophysiology of Behcet's DiseaseZIAHG200374 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI KASTNER, DANIEL · 2011 to 2020
$10.5MTNF-receptors and programmed cell death in regulation of autoimmunityZIAAR041133 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI SIEGEL, RICHARD M · 2009 to 2019
$9.3MIntramural NIH HHS Z99 HG999999NIAMS NIH HHS K23 AR068440
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.
Indexed as
MutationAge of OnsetDNA-Binding ProteinsFemaleHaploinsufficiencyHereditary Autoinflammatory DiseasesHumansI-kappa B KinaseI-kappa B ProteinsIntracellular Signaling Peptides and ProteinsMaleNF-kappa BNF-KappaB Inhibitor alphaNuclear Pore Complex ProteinsNuclear ProteinsPedigreeAGFG1 protein, humanDNA-Binding ProteinsI-kappa B KinaseI-kappa B ProteinsIKBKG protein, humanIntracellular Signaling Peptides and ProteinsNF-kappa BNF-KappaB Inhibitor alphaNFKBIA protein, humanNuclear Pore Complex ProteinsNuclear ProteinsRNA-Binding ProteinsTNFAIP3 protein, humanTNF Receptor-Associated Factor 6Tumor Necrosis Factor alpha-Induced Protein 3
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