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

• Published in: Nature genetics Vol. 48; no. 1; pp. 67 - 73
• Main Authors: Zhou, Qing, Wang, Hongying, Schwartz, Daniella M, Stoffels, Monique, Park, Yong Hwan, Zhang, Yuan, Yang, Dan, Demirkaya, Erkan, Takeuchi, Masaki, Tsai, Wanxia Li, Lyons, Jonathan J, Yu, Xiaomin, Ouyang, Claudia, Chen, Celeste, Chin, David T, Zaal, Kristien, Chandrasekharappa, Settara C, P Hanson, Eric, Yu, Zhen, Mullikin, James C, Hasni, Sarfaraz A, Wertz, Ingrid E, Ombrello, Amanda K, Stone, Deborah L, Hoffmann, Patrycja, Jones, Anne, Barham, Beverly K, Leavis, Helen L, van Royen-Kerkof, Annet, Sibley, Cailin, Batu, Ezgi D, Gül, Ahmet, Siegel, Richard M, Boehm, Manfred, Milner, Joshua D, Ozen, Seza, Gadina, Massimo, Chae, JaeJin, Laxer, Ronald M, Kastner, Daniel L, Aksentijevich, Ivona
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2016; Nature Publishing Group
• Subjects: 45/23; 45/47; 45/77; 631/208/1516; 631/250/248; 692/699/249/2510; 82/1; 82/51; 82/80; Age of Onset; Agriculture; Animal Genetics and Genomics; Biomedicine; Blood proteins; Cancer Research; Cytokines; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Function; Gene mutation; Genetic aspects; Haploinsufficiency - genetics; Hereditary Autoinflammatory Diseases - genetics; Hereditary Autoinflammatory Diseases - metabolism; Human Genetics; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Inflammation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; letter; Male; Mutation; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pedigree; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Studies; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Translocation; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor necrosis factor-TNF; Ubiquitin
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3459

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 immunity 1 . 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 2 . A20 is a potent inhibitor of the NF-κB signaling pathway 3 . 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.