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


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

NATURE GENETICS, cilt.48, ss.67-75, 2016 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 48 Konu: 1
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1038/ng.3459
  • Dergi Adı: NATURE GENETICS
  • Sayfa Sayıları: ss.67-75

Özet

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.