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.
Publication types
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Multicenter Study
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age of Onset
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Female
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Haploinsufficiency / genetics*
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Hereditary Autoinflammatory Diseases / genetics*
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Hereditary Autoinflammatory Diseases / metabolism
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Mutation*
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NF-KappaB Inhibitor alpha
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Pedigree
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Tumor Necrosis Factor alpha-Induced Protein 3
Substances
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AGFG1 protein, human
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DNA-Binding Proteins
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I-kappa B Proteins
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IKBKG protein, human
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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NFKBIA protein, human
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Nuclear Pore Complex Proteins
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Nuclear Proteins
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RNA-Binding Proteins
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TNF Receptor-Associated Factor 6
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NF-KappaB Inhibitor alpha
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I-kappa B Kinase
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3