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: Qing Zhou, Hongying Wang, Daniella M Schwartz, Monique Stoffels, Yong Hwan Park, Yuan Zhang, Dan Yang, Erkan Demirkaya, Masaki Takeuchi, Wanxia Li Tsai, Jonathan J Lyons, Xiaomin Yu, Claudia Ouyang, Celeste Chen, David T Chin, Kristien Zaal, Settara C Chandrasekharappa, Eric P Hanson, Zhen Yu, James C Mullikin, Sarfaraz A Hasni, Ingrid E Wertz, Amanda K Ombrello, Deborah L Stone, Patrycja Hoffmann, Anne Jones, Beverly K Barham, Helen L Leavis, Annet van Royen-Kerkof, Cailin Sibley, Ezgi D Batu, Ahmet Gül, Richard M Siegel, Manfred Boehm, Joshua D Milner, Seza Ozen, Massimo Gadina, JaeJin Chae, Ronald M Laxer, Daniel L Kastner, Ivona Aksentijevich
• Journal: Nature genetics (Nat Genet) Vol. 48 Issue 1 Pg. 67-73 (01 2016) ISSN: 1546-1718 [Electronic] United States
• PMID: 26642243 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGFG1 protein, human
• DNA-Binding Proteins
• I-kappa B Proteins
• IKBKG protein, human
• Intracellular Signaling Peptides and Proteins
• NF-kappa B
• NFKBIA protein, human
• Nuclear Pore Complex Proteins
• Nuclear Proteins
• RNA-Binding Proteins
• TNF Receptor-Associated Factor 6
• NF-KappaB Inhibitor alpha
• I-kappa B Kinase
• TNFAIP3 protein, human
• Tumor Necrosis Factor alpha-Induced Protein 3

Topics

• Age of Onset
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Haploinsufficiency (genetics)
• Hereditary Autoinflammatory Diseases (genetics, metabolism)
• Humans
• I-kappa B Kinase (genetics, metabolism)
• I-kappa B Proteins (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Mutation
• NF-KappaB Inhibitor alpha
• NF-kappa B (genetics, metabolism)
• Nuclear Pore Complex Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Pedigree
• RNA-Binding Proteins (genetics, metabolism)
• TNF Receptor-Associated Factor 6 (genetics, metabolism)
• Tumor Necrosis Factor alpha-Induced Protein 3