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.
Qing Zhou  1 ,  Hongying Wang  1 ,  Daniella M Schwartz  2 ,  Monique Stoffels  1 ,  Yong Hwan Park  1 ,  Yuan Zhang  3 ,  Dan Yang  4 ,  Erkan Demirkaya  5 ,  Masaki Takeuchi  1 ,  Wanxia Li Tsai  6 ,  Jonathan J Lyons  3 ,  Xiaomin Yu  3 ,  Claudia Ouyang  7 ,  Celeste Chen  1 ,  David T Chin  1 ,  Kristien Zaal  8 ,  Settara C Chandrasekharappa  9 ,  Eric P Hanson  7 ,  Zhen Yu  4 ,  James C Mullikin  10 ,  Sarfaraz A Hasni  11 ,  Ingrid E Wertz  12 ,  Amanda K Ombrello  1 ,  Deborah L Stone  1 ,  Patrycja Hoffmann  1 ,  Anne Jones  1 ,  Beverly K Barham  1 ,  Helen L Leavis  13 ,  Annet van Royen-Kerkof  14 ,  Cailin Sibley  15 ,  Ezgi D Batu  16 ,  Ahmet Gül  17 ,  Richard M Siegel  7 ,  Manfred Boehm  4 ,  Joshua D Milner  3 ,  Seza Ozen  16 ,  Massimo Gadina  6 ,  JaeJin Chae  1 ,  Ronald M Laxer  18 ,  Daniel L Kastner  1 ,  Ivona Aksentijevich  1
Affiliations
  • 1. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • 2. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
  • 3. Genetics and Pathogenesis of Allergy Section, National Institute of Allergy and Infectious Diseases, Laboratory of Allergic Diseases, Bethesda, Maryland, USA.
  • 4. Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
  • 5. FMF Arthritis Vasculitis and Orphan Disease Research Center (FAVOR), Gulhane Military Medical Academy, Ankara, Turkey.
  • 6. Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
  • 7. Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
  • 8. Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
  • 9. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • 10. National Institute of Health Intramural Sequencing Center, National Human Genome Research Institute, Bethesda, Maryland, USA.
  • 11. Systemic Autoimmune Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
  • 12. Department of Molecular Oncology, Genentech, Inc., San Francisco, California, USA.
  • 13. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 14. Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 15. Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, Oregon, USA.
  • 16. Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
  • 17. Department of Internal Medicine, Istanbul University, Istanbul, Turkey.
  • 18. Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
PMID: 26642243 DOI: 10.1038/ng.3459
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.