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

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. MullikinSarfaraz 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, Jae Jin Chae, Ronald M. Laxer, Daniel L. Kastner, Ivona Aksentijevich

Research output: Contribution to journalArticlepeer-review

394 Scopus citations


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-B 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-B 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 IBα and nuclear translocation of the NF-B p65 subunit together with increased expression of NF-B-mediated proinflammatory cytokines. A20 restricts NF-B 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-B-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

Original languageEnglish (US)
Pages (from-to)67-73
Number of pages7
JournalNature genetics
Issue number1
StatePublished - Dec 29 2015

ASJC Scopus subject areas

  • Genetics


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