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

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 I?B? 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.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC4777523 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Zhou Qing Q Wang Hongying H Schwartz Daniella M DM Stoffels Monique M Park Yong Hwan YH Zhang Yuan Y Yang Dan D Demirkaya Erkan E Takeuchi Masaki M Tsai Wanxia Li WL Lyons Jonathan J JJ Yu Xiaomin X Ouyang Claudia C Chen Celeste C Chin David T DT Zaal Kristien K Chandrasekharappa Settara C SC Hanson Eric P EP Yu Zhen Z Mullikin James C JC Hasni Sarfaraz A SA Wertz Ingrid E IE Ombrello Amanda K AK Stone Deborah L DL Hoffmann Patrycja P Jones Anne A Barham Beverly K BK Leavis Helen L HL van Royen-Kerkof Annet A Sibley Cailin C Batu Ezgi D ED Gül Ahmet A Siegel Richard M RM Boehm Manfred M Milner Joshua D JD Ozen Seza S Gadina Massimo M Chae JaeJin J Laxer Ronald M RM Kastner Daniel L DL Aksentijevich Ivona I

Nature genetics 20151207 1

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, trunc ...[more]

PMID: 26642243

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Project description:BackgroundA20 haploinsufficiency (HA20) is a newly introduced autosomal dominant autoinflammatory disorder, also known as Behcet's-like disease. Some of the most common symptoms of the disease are recurrent oral, genital, and/or gastrointestinal (GI) ulcers, episodic fever, musculoskeletal symptoms, cutaneous lesions, and recurrent infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of multi-organ failure due to excessive immune activation. HLH has been reported in a few HA20 patients. Herein, we report two children with the primary presentation of HLH, with a mutation in TNFAIP3, in favor of HA20.Case presentationsOur first patient was a 4-month-old boy who presented with fever, irritability, pallor, and hepatosplenomegaly. Pancytopenia, elevated ferritin, and decreased fibrinogen levels were found in laboratory evaluation. He was diagnosed with HLH and was treated with methylprednisolone and cyclosporine. Two years later, whole exome sequencing (WES) indicated a mutation in TNFAIP3 at NM_001270507: exon3: c.C386T, p.T129M, consistent with A20 haploinsufficiency. Etanercept, a TNF inhibitor, was prescribed, but the parents were reluctant to initiate the therapy. The patient passed away with the clinical picture of cerebral hemorrhage. The second patient was a 3-month-old boy who presented with a fever and hepatosplenomegaly. Laboratory evaluation found pancytopenia, hyperferritinemia, hypoalbuminemia, hypertriglyceridemia, and hypofibrinogenemia. With the establishment of the HLH diagnosis, he was treated with etoposide, dexamethasone, and cyclosporine, and recovered. WES results revealed a heterozygous de novo variant of TNFAIP3 (c. T824C in exon 6, 6q23.3) that leads to a proline to leucine amino acid change (p. L275P). He was treated with etanercept and has been symptom-free afterward.ConclusionsThis report is a hypothesis for developing of the HLH phenotype in the presence of TNFAIP3 mutation. Our results provide a new perspective on the role of TNFAIP3 mutation in HLH phenotypes, but more extensive studies are required to confirm these preliminary results.

Dataset Information

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

Publications

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

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