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

Nat Genet. 2016 Jan;48(1):67-73. doi: 10.1038/ng.3459. Epub 2015 Dec 7.

Abstract

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-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. A20 is a potent inhibitor of the NF-κB 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 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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Haploinsufficiency / genetics*
  • Hereditary Autoinflammatory Diseases / genetics*
  • Hereditary Autoinflammatory Diseases / metabolism
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mutation*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • 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
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • AGFG1 protein, human
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • IKBKG protein, human
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • TNF Receptor-Associated Factor 6
  • NF-KappaB Inhibitor alpha
  • I-kappa B Kinase
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3