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Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

2015; Nature Portfolio; Volume: 48; Issue: 1 Linguagem: Inglês

10.1038/ng.3459

1546-1718

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 J.M. Zaal, Settara C. Chandrasekharappa, Eric P. Hanson, Zhen Yu, James C. Mullikin, Sarfaraz Hasni, Ingrid E. Wertz, Amanda K. Ombrello, Deborah L. Stone, Patrycja Hoffmann, Anne Jones, Beverly Barham, Helen L. Leavis, Annet van Royen-Kerkof, Cailin H. Sibley, Ezgi Deniz Batu, Ahmet Gül, Richard M. Siegel, Manfred Boehm, Joshua D. Milner, Seza Özen, Massimo Gadina, JaeJin Chae, Ronald M. Laxer, Daniel L. Kastner, Ivona Aksentijevich,

Inflammasome and immune disorders

Ivona Aksentijevich and colleagues identify heterozygous loss-of-function mutations in TNFAIP3 (encoding A20) in six unrelated families with early-onset systemic inflammation. Affected individuals exhibit increased expression of NF-κB–mediated proinflammatory cytokines, consistent with the established role of A20 as a potent inhibitor of the NF-κB signaling pathway. Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity1. 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 adulthood2. A20 is a potent inhibitor of the NF-κB signaling pathway3. 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.