Paediatrics Publications

Title

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

Authors

Qing Zhou, National Human Genome Research Institute (NHGRI)
Hongying Wang, National Human Genome Research Institute (NHGRI)
Daniella M. Schwartz, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Monique Stoffels, National Human Genome Research Institute (NHGRI)
Yong Hwan Park, National Human Genome Research Institute (NHGRI)
Yuan Zhang, National Institute of Allergy and Infectious Diseases (NIAID)
Dan Yang, National Heart, Lung, and Blood Institute (NHLBI)
Erkan Demirkaya, Gulhane Military Medical AcademyFollow
Masaki Takeuchi, National Human Genome Research Institute (NHGRI)
Wanxia Li Tsai, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Jonathan J. Lyons, National Institute of Allergy and Infectious Diseases (NIAID)
Xiaomin Yu, National Institute of Allergy and Infectious Diseases (NIAID)
Claudia Ouyang, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Celeste Chen, National Human Genome Research Institute (NHGRI)
David T. Chin, National Human Genome Research Institute (NHGRI)
Kristien Zaal, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Settara C. Chandrasekharappa, National Human Genome Research Institute (NHGRI)
Eric P. Hanson, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Zhen Yu, National Heart, Lung, and Blood Institute (NHLBI)
James C. Mullikin, National Human Genome Research Institute (NHGRI)
Sarfaraz A. Hasni, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Ingrid E. Wertz, Genentech Incorporated
Amanda K. Ombrello, National Human Genome Research Institute (NHGRI)
Deborah L. Stone, National Human Genome Research Institute (NHGRI)
Patrycja Hoffmann, National Human Genome Research Institute (NHGRI)
Anne Jones, National Human Genome Research Institute (NHGRI)
Beverly K. Barham, National Human Genome Research Institute (NHGRI)
Helen L. Leavis, University Medical Center Utrecht
Annet Van Royen-Kerkof, University Medical Center Utrecht

Document Type

Article

Publication Date

12-29-2015

Journal

Nature Genetics

Volume

48

Issue

1

First Page

67

Last Page

73

URL with Digital Object Identifier

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-B 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-B 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 IBα and nuclear translocation of the NF-B p65 subunit together with increased expression of NF-B-mediated proinflammatory cytokines. A20 restricts NF-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-B-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

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