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.

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