1. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.
- Author
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Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Hanson EP, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gül A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, and Aksentijevich I
- Subjects
- Age of Onset, DNA-Binding Proteins metabolism, Female, Hereditary Autoinflammatory Diseases metabolism, Humans, I-kappa B Kinase genetics, I-kappa B Kinase metabolism, I-kappa B Proteins genetics, I-kappa B Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Male, NF-KappaB Inhibitor alpha, NF-kappa B genetics, NF-kappa B metabolism, Nuclear Pore Complex Proteins genetics, Nuclear Pore Complex Proteins metabolism, Nuclear Proteins metabolism, Pedigree, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, TNF Receptor-Associated Factor 6 genetics, TNF Receptor-Associated Factor 6 metabolism, Tumor Necrosis Factor alpha-Induced Protein 3, DNA-Binding Proteins genetics, Haploinsufficiency genetics, Hereditary Autoinflammatory Diseases genetics, Intracellular Signaling Peptides and Proteins genetics, Mutation, Nuclear Proteins genetics
- 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.
- Published
- 2016
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