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

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ZHOU Q., WANG H., SCHWARTZ D. M., STOFFELS M., PARK Y. H., ZHANG Y., ...More

NATURE GENETICS, vol.48, no.1, pp.67-75, 2016 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 48 Issue: 1
  • Publication Date: 2016
  • Doi Number: 10.1038/ng.3459
  • Journal Name: NATURE GENETICS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.67-75
  • Hacettepe University Affiliated: Yes

Abstract

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.