Alt. symbols: A20 | OTUD7C

Approved name: TNF alpha induced protein 3
Alt. names: tumor necrosis factor, alpha-induced protein 3

Location: 6q23.3: 137867214 - 137883314 (+)
Gene type: protein_coding, 9 transcripts.

Scores: LoFtool: 0.141000 | pLI: 0.99966668 | LOEUF: 0.196

HGNC: 11896

NCBI: 7128, RefSeq: NG_032761.1

Ensembl: ENSG00000118503.18

LRG_ | Status: none

OMIM: 191163

Expression | ProteinAtlas

TNFAIP3 encodes A20, a multifunctional cytoplasmic zinc finger protein and ubiquitin-editing enzyme that can bind to K63-linked and linear polyubiquitin chains and exhibit both de-ubiquitylation and E3 ubiquitin ligase activities. A20 is involved in many cytokine-mediated immune and inflammatory responses through its regulation of multiple ubiquitin-dependent cellular activation and survival signals downstream of TNF receptors, Toll-like receptors, the interleukin-1 receptor, NOD-like receptors, CD40 and antigen receptors (PMID: 31427375). Of note, TNF signaling dramatically increases A20 mRNA expression in all tissues.

Predominantly frameshift and nonsense heterozygous TNFAIP3 mutations cause familial Behcet-like autoinflammatory syndrome (AISBL) or haploinsufficiency of A20 (HA20) [MIM:616744]. This AD disorder is characterized by Behcet-like findings of mucosal ulcerations along the entire GI tract, particularly in the oral and genital areas, with symptoms emerging in the first or second decade of life. Additional and more variable features include erythema nodosum-like skin lesions, uveitis, chorioretinitis , polyarthritis, chronic urticaria, angioedema, folliculitis, recurrent fever, persistent EBV viremia, and neurosarcoid-like features of left-sided focal seizures, hemiparesis, and cognitive decline (PMID: 31175876, 34030699). Of note, Takagi et al. (2017) and others also reported HA20 as being associated with an ALPS-like phenotype and/or immune cytopenias (PMID: 27845235, 32714711). Lab findings include elevated inflammatory markers, dysgammaglobulinemia, positivity for multiple autoantibodies, and cytopenias as well as myeloid lineage abnormalities in the bone marrow. The disorder results from inappropriate activation of inflammatory cytokines and has been shown responsive to treatment with tumor necrosis factor (TNF) inhibitors (PMID: 26642243). To date, at least 38 affected individuals from 16 unrelated families have been reported with disease-causing TNFAIP3 mutations. Zhou et al. (2016) described the first 6 families with different frameshift mutations in the gene, all leading to A20 haploinsufficiency. Additional families with truncating (frameshift or nonsense) mutations were subsequently described (PMID: 27451268, 30402268, 30526650, 32514655). However, only few potentially disease-related missense variants have been reported: Shigemura et al. (2016) identified a Japanese family of 6 patients over 4 generations with Behcet-like findings of frequent oral ulcers, genital ulcers and erythema nodosum-like skin lesions carrying a heterozygous p.C243Y variant (PMID: 27175295). The authors showed that this mutation led to a partial loss of A20 function, with patient mononuclear cells showing significantly higher levels of pro-inflammatory cytokine production compared to normal controls with impaired response to suppression. However, they noted no significant difference from WT controls by NF-kB reporter gene activation after TNF-alpha stimulation (PMID: 29241730). Harris et al. (2018) also reported a Hispanic family with chronic urticaria and angioedema who were found to be heterozygous for a p.R22Q variant (PMID: 29682366). Dong et al. (2019) identified a heterozygous p.M476I variant in a 13 year old Chinese boy with Behçet-like phenotype and persistent EBV viremia, as well as his more mildly affected mother (PMID: 30810840). Mulhern et al. (2019) identified a heterozygous p.T647P variant in an 8-year-old girl of nonconsanguineous Pakistani-Indian descent with neurosarcoid like features who presented with left-sided focal seizures and hemiparesis, uveitis, chorioretinitis, and cognitive decline (PMID: 31175876). More recently, Kadowaki et al. (2021) identified and characterized 3 additional missense variants along with the previously reported C243Y, M476I, and T647P variants - Glu192Lys was classified as likely pathogenic, Ile310Thr as a variant of uncertain significance and Gln709Arg as a likely benign variant based on ACMG guidelines (PMID: 33549127). Using an NF-kB reporter gene assay, the authors showed that suppressive activity was signi [Load More]