Haploinsufficiency of A20 with a novel mutation of deletion of exons 2–3 of <i>TNFAIP3</i>

Shimizu, M; Matsubayashi, Tadashi; Ohnishi, Hiroyuki; Nakama, Mina; Izawa, Kazushi; Honda, Yoshitaka; Nishikomori, Ryuta

doi:10.1080/14397595.2020.1719595

Cited by 9 publications

(6 citation statements)

References 14 publications

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“…In both groups of patients, colchicine, systemic corticosteroids, disease-modifying drugs, and molecular targeted therapies were relatively commonly administered. In East Asia, anti-TNF-a agents (infliximab, adalimumab, and etanercept) were administered in most severe cases, while anti-IL-6 agents (tocilizumab) were also administered in some cases (10,13,16,21,24). Only one patient was treated with anti-IL-1 agents (canakinumab) in East Asia (47).…”

Section: Treatment Of Ha20mentioning

confidence: 99%

A20 Haploinsufficiency in East Asia

Kadowaki

Ohnishi

2021

Front. Immunol.

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A20, encoded by the TNFAIP3 gene, is a negative regulator of tumor necrosis factor (TNF)-nuclear factor-κB signaling. It was recently demonstrated that A20 haploinsufficiency (HA20), caused by a heterozygous mutation in the TNFAIP3 gene, can present as an early onset autoinflammatory disease resembling Behçet’s disease (BD). In addition to autoinflammatory symptoms, HA20 was also reported to be associated with autoimmune diseases and immunodeficiency. Because the phenotypes associated with HA20 are broad, with different severities observed even among individuals in the same family with identical mutations, it has been assumed that the symptoms of HA20 may depend on genetic background and environmental factors. In this review, we summarize the characteristics of patients with HA20 in East Asia and compare these with patients in other regions, mainly the USA and Europe. Patients with HA20 in East Asia developed recurrent fever more frequently than patients in other regions, but were less likely to develop typical BD symptoms such as skin rashes and genital ulcers. In addition, patients with HA20 in East Asia had low rates of complication with autoimmune diseases and low autoantibody detection rates. While anti-TNF-α agents were the primary treatments for severe HA20 in East Asia, anti-interleukin-1 agents and Janus kinase inhibitors were also administered in other regions. Future studies will need to establish methods for analyzing the pathophysiology of HA20 and determining optimal treatment strategies for each patient.

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Section: Treatment Of Ha20mentioning

confidence: 99%

A20 Haploinsufficiency in East Asia

Kadowaki

Ohnishi

2021

Front. Immunol.

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“…We identified 33 disease-causing variants and 32 of which were indicated in Figure 1A. A large deletion mutation of exons 2-3 of TNFAIP3 located in the OTU coding region was not shown on the schematic diagram because no exact mutation locus was identified in the case report (13). We found 7 frameshift mutations and 11 nonsense mutations in the OTU coding region (OTU+ZnF group), 2 missense mutations in the OTU coding region (OTU group), 11 frameshift mutations, 1 nonsense, and 1 missense mutation in the ZnF coding region (ZnF group) ( Figure 1B).…”

Section: Classification Of A20 Disruption According To Tnfaip3 Gene Mmentioning

confidence: 99%

Association of Clinical Phenotypes in Haploinsufficiency A20 (HA20) With Disrupted Domains of A20

Chen

et al. 2020

Front. Immunol.

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Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

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“…Similarly, patients with heterozygous mutations in the A20 gene cause haploinsufficiency of A20 (also named HA20), displaying an excessive ubiquitination which leads to increased NF-κB activity and also NLRP3-inflammasome activation. HA20 patients present with some Behçet-like characteristics or an autoimmune lymphoproliferative syndrome-like phenotype [58]. Recently, using a genotype-driven approach, Beck et al…”

Section: The Relopathiesmentioning

confidence: 99%

The everchanging framework of autoinflammation

Manna

Rigante

2021

Intern Emerg Med

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The innate immunity works as a defence bullwark that safeguards healthy tissues with the power of detecting infectious agents in the human body: errors in the context of innate immunity identify autoinflammatory disorders (AIDs), which arise as bouts of aberrant inflammation with little or no involvement of T and B cells and neither recognized infections, nor associated autoimmune phenomena. Hereditary AIDs tend to have a pediatric-onset heralded by stereotyped inflammatory symptoms and fever, while AIDs without an ascertained cause, such as systemic juvenile idiopathic arthritis, derive from the interaction of genetic factors with environmental noxae and are unevenly defined. A dysregulated inflammasome activation promotes the best-known family of AIDs, as well as several degenerative and metabolic disorders, but also nuclear factor κB- and interferon-mediated conditions have been framed as AIDs: the zenith of inflammatory flares marks different phenotypes, but diagnosis may go unnoticed until adulthood due to downplayed symptoms and complex kaleidoscopic presentations. This review summarizes the main AIDs encountered in childhood with special emphasis on the clinical stigmata that may help establish a correct framework and blueprints to empower young scientists in the recognition of AIDs. The description focuses inflammasomopathies as paradigms of interleukinopathies, nuclear factor-κB -related disorders and interferonopathies. The challenges in the management of AIDs during childhood have been recently boosted by numerous therapeutic options derived from genomically-based approaches, which have led to identify targeted biologic agents as rationalized treatments and achieve more tangible perspectives of disease control.

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Haploinsufficiency of A20 with a novel mutation of deletion of exons 2–3 of TNFAIP3

Cited by 9 publications

References 14 publications

A20 Haploinsufficiency in East Asia

A20 Haploinsufficiency in East Asia

Association of Clinical Phenotypes in Haploinsufficiency A20 (HA20) With Disrupted Domains of A20

The everchanging framework of autoinflammation

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