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Yayınlanmış 1 Ocak 2016 | Sürüm v1
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Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Oluşturanlar

  • 1. NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA
  • 2. Natl Inst Arthrit & Musculoskeletal & Skin Dis, Mol Immunol & Inflammat Branch, Bethesda, MD USA
  • 3. Lab Allerg Dis, Natl Inst Allergy & Infect Dis, Genet & Pathogenesis Allergy Sect, Bethesda, MD USA
  • 4. Gulhane Mil Med Acad, FMF Arthrit Vasculitis & Orphan Dis Res Ctr FAVOR, Ankara, Turkey
  • 5. Natl Inst Arthrit & Musculoskeletal & Skin Dis, Translat Immunol Sect, Bethesda, MD USA
  • 6. Natl Inst Arthrit & Musculoskeletal & Skin Dis, Autoimmun Branch, Bethesda, MD USA
  • 7. Natl Inst Arthrit & Musculoskeletal & Skin Dis, Light Imaging Sect, Bethesda, MD USA
  • 8. NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA
  • 9. NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, Bethesda, MD 20892 USA

Açıklama

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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