Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment

Yu(, Meiping; Xu, Xiaoyan; Zhou, Qing; Deuitch, Natalie; Lu, Meiping

doi:10.1007/s12519-019-00288-6

Cited by 58 publications

(73 citation statements)

References 26 publications

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“…A20 plays an important role in regulating immunity by inhibiting NF-κB signaling, activation of NLRP3 inflammasome, and apoptosis ( 8 , 9 ). Haploinsufficiency of A20 is characterized by an upregulated inflammatory reaction and manifests symptoms that resemble many autoimmune diseases, including BD, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) ( 3 ). The patient in our report presented with iBD-like symptoms, including relapsing ulceration of intestinal anastomosis, recurrent oral ulcers and vasculitis in extremities; although, the patient's intestinal ulcer was atypical due to the long segment involvement in the intestine and incomplete intestinal obstruction.…”

Section: Discussionmentioning

confidence: 99%

“…The typical intestinal ulcer of iBD is defined as less than five ulcers that are oval in shape, deep with discrete borders, and located in the ileocecal area ( 2 ). Haploinsufficiency of A20 (HA20) is a newly described autoimmune disorder with one of the various phenotypes resembling BD ( 3 ). HA20 is caused by heterozygous loss-of-function mutations of the TNF Alpha Induced Protein 3 (TNFAIP3) gene encoding A20 and the diagnosis of HA20 mainly depends on genetic analysis ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report

Chen

Huang

et al. 2020

Front. Immunol.

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Intestinal Behcet's disease (iBD) is an autoimmune disorder diagnosed by typical intestinal ulcers and systemic Behcet's disease (BD) manifestations. Haploinsufficiency of A20 (HA20) is a recently described autoinflammatory disease with a phenotype resembling BD, caused by heterozygous loss-of-function mutations in TNFAIP3 gene (encoding A20). Methods: We described a 29-year-old female with iBD-like symptoms including relapsing ulceration of intestinal anastomosis, recurrent oral ulcers and vasculitis in extremities. Due to the atypical intestinal ulcers with long segmental involvement and intestinal obstruction, whole exome sequencing (WES) was performed to screen for the underlying genetic defect and the identified gene was confirmed by Sanger sequencing. The expression levels of A20 was evaluated by Western blot. Sanger sequencing and Western blot were also performed in the patient's family members. Results: A heterozygous mutation of TNFAIP3 (c.305A>G, p. Asn 102 Ser) was identified in the patient. The identical TNFAIP3 mutation was also found in her father and brother who had suffered from recurrent oral ulcers since childhood. Functional experiments revealed that the expression of A20 was decreased in the peripheral blood mononuclear cells of the patient and her family members who carried the TNFAIP3 mutation. Conclusion: We described a Chinese patient with a novel heterozygous mutation in TNFAIP3 who developed iBD-like symptoms. We proposed that the TNFAIP3 heterozygous mutation (c.305A>G, p. Asn 102 Ser) with an insufficient expression of A20 may be associated with the iBD phenotype in patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report

Chen

Huang

et al. 2020

Front. Immunol.

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“…The mutation determines haploinsufficiency and is thereby leading to the dysfunction of the protein, which in turn is causing overproduction of NF‐κB dependent proinflammatory cytokines [81, 82]. The clinical manifestations are not distinguishable from Behçet’s disease (BD), therefore HA20 is ranked among the spectrum of BD [82–84].…”

Section: Tnfα‐mediated Diseasesmentioning

confidence: 99%

Autoinflammatory syndromes

Meier‐Schiesser

French

2021

J Deutsche Derma Gesell

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Summary Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is multifaceted, but recurrent fever, skin involvement, joint inflammation and other systemic symptoms of inflammation are characteristic. In contrast to classic autoimmune diseases, autoantibodies or specific T cells are not involved in the pathogenesis. In fact, innate immunity plays the most important role in autoinflammation. While activation of the innate immune system is usually self‐limiting in healthy individuals, mutations and dysregulation can lead to chronic and excessive activation of innate immune responses and to the development of autoinflammatory diseases.

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“…The loss-of-function mutation in TNFAIP3 diminishes the inhibitory effect of NF-κB, leads to increased inflammatory cytokine production and causes systemic inflammatory disease. To date, HA20 is the most common monogenic disease with BD-like phenotypes [ 26 , 27 ]. Patients carrying HA20 present with periodic fevers, recurrent aphthous stomatitis, genital ulceration, intestinal symptoms, skin rashes, polyarthritis, and neurological symptoms.…”

Section: Nf-κb-related Genesmentioning

confidence: 99%

Primary Immunodeficiency Disease Mimicking Pediatric Bechet’s Disease

Shiraki

Kadowaki

et al. 2021

Children

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Behcet’s disease (BD) is a chronic inflammatory disease with multisystemic involvement. Its etiology is considered to involve complex environmental and genetic factors. Several susceptibility genes for BD, such as human leukocyte antigen (HLA)-A26, IL23R-IL12RB2, IL10 and ERAP1, in addition to the well-studied HLA-B51, were mainly identified by genome-wide association studies. A heterozygous mutation in TNFAIP3, which leads to A20 haploinsufficiency, was found to cause an early-onset autoinflammatory disease resembling BD in 2016. Several monogenic diseases associated with primary immunodeficiency disease and trisomy 8 have recently been reported to display BD-like phenotypes. Among the genes causing these diseases, TNFAIP3, NEMO, RELA, NFKB1 and TNFRSF1A are involved in the NF-κB (nuclear factor κ light-chain enhancer of activated B cells) signaling pathway, indicating that this pathway plays an important role in the pathogenesis of BD. Because appropriate treatment may vary depending on the disease, analyzing the genetic background of patients with such diseases is expected to help elucidate the etiology of pediatric BD and assist with its treatment. Here, we summarize recently emerging knowledge about genetic predisposition to BD.

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Haploinsufficiency of A20 (HA20): updates on the genetics, phenotype, pathogenesis and treatment

Cited by 58 publications

References 26 publications

A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report

A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report

Autoinflammatory syndromes

Primary Immunodeficiency Disease Mimicking Pediatric Bechet’s Disease

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