Journal
NATURE GENETICS
Volume 48, Issue 1, Pages 67-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3459
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Funding
- Intramural Research Programs of the National Human Genome Research Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- US National Institutes of Health Clinical Center
- Research Fellowship Program for International Researchers - Scientific and Technological Research Council of Turkey (TUBITAK) [B.14.2.TBT.0.06.01-219-84]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006077] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG200330, ZIAHG200373, ZIAHG200374, ZIAHG000029, ZIBHG000196, ZICHG200346] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001183] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041133, ZICAR041186, ZICAR041181, K23AR068440, ZIAAR041175, ZIEAR041176, ZIAAR041187, ZIDAR041180] Funding Source: NIH RePORTER
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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-kappa B regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behcet's disease, which is typically considered a polygenic disorder with onset in early adulthood(2). A20 is a potent inhibitor of the NF-kappa B 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 I kappa B alpha and nuclear translocation of the NF-kappa B p65 subunit together with increased expression of NF-kappa B-mediated proinflammatory cytokines. A20 restricts NF-kappa 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-kappa B-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.
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