Alternative titles; symbols
HGNC Approved Gene Symbol: TNFAIP3
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38): 6:137,866,349-137,883,312 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.3 | Autoinflammatory syndrome, familial, Behcet-like 1 | 616744 | Autosomal dominant | 3 |
The TNFAIP3 gene encodes an ubiquitin-editing enzyme with a critical function in the inhibition of key proinflammatory molecules to negatively regulate inflammation and the immune response (summary by Aeschlimann et al., 2018).
A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappa-B (NFKB; see 164011) activity and tumor necrosis factor (TNF; 191160)-mediated programmed cell death. TNF dramatically increases A20 mRNA expression in all tissues (Dixit et al., 1990; Lee et al., 2000).
Cytokines such as TNF profoundly affect endothelial cell function, promoting, for example, interaction with leukocytes and inducing a procoagulant phenotype. Changes of this nature are likely to be central to the proinflammatory effects of TNF. Dixit et al. (1990) analyzed TNF-induced primary response genes in human umbilical vein endothelial cells. Of the 6 induced cDNAs identified, 2 encoded paracrine factors, neutrophil chemotactic factor (146930) and monocyte chemotactic factor (158105); 1 encoded a membrane receptor for neutrophils, endothelial leukocyte adhesion molecule 1 (ELAM1; 131210); and 3 encoded hitherto undescribed TNF primary response genes. On exposure of endothelial cells to TNF, there was a rapid and substantial increase in the levels of mRNA encoding the 6 genes, which were further superinduced by cycloheximide. Thus these represent primary response genes, as their induction does not depend on protein synthesis. One of the 3 new proteins, designated A20, was found on sequence analysis to code for a novel zinc finger protein (Opipari et al., 1990).
Hartz (2014) mapped the TNFAIP3 gene to chromosome 6q23.3 based on an alignment of the TNFAIP3 sequence (GenBank AL157444) with the genomic sequence (GRCh38).
Wolfrum et al. (2007) stated that the mouse Tnfaip3 gene maps to proximal chromosome 10.
O'Reilly and Moynagh (2003) expressed A20 and TLR4 (603030) in a human embryonic kidney cell line and observed inhibition of NFKB activation after LPS stimulation. Mutation analysis showed that the C-terminal zinc finger domain of A20 was sufficient for NFKB inhibition, whereas the full-length protein was required for inhibition of AP1 (165160) activation and for induction of IL8 (146930). O'Reilly and Moynagh (2003) concluded that A20 modulates TLR4 signaling at or downstream of MEKK1 (MAP3K1; 600982).
Wertz et al. (2004) demonstrated that A20 downregulates NF-kappa-B signaling through the cooperative activity of its 2 ubiquitin-editing domains. The N-terminal domain of A20, which is a deubiquitinating enzyme of the OTU (ovarian tumor) family, removes lysine-63-linked ubiquitin chains from receptor-interacting protein (RIP; 603453), an essential mediator of the proximal TNF receptor-1 (TNFR1; 191190) signaling complex. The C-terminal domain of A20, composed of 7 C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with lysine-48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Wertz et al. (2004) defined a novel ubiquitin ligase domain and identified 2 sequential mechanisms by which A20 downregulates NF-kappa-B signaling. They also provided an example of a protein containing separate ubiquitin ligase and deubiquitinating domains, both of which participate in mediating a distinct regulatory effect.
Vendrell et al. (2007) found that expression of A20 was downregulated by estradiol treatment of an estrogen receptor (ER; see 133430)-positive, hormone-responsive human breast cancer cell line. Conversely, A20 was highly expressed in ER-negative cell lines. Overexpression of A20 in MCF7 breast cancer cells conferred resistance to tamoxifen-induced cytotoxicity that was associated with dysregulation of BAX (600040), BCL2 (151430), BAK (600516), phospho-BAD (603167), and several cyclins (e.g., CCNA2; 123835). A20 was overexpressed in tamoxifen-resistant cell lines, and high A20 expression was also observed in more aggressive breast tumors. Vendrell et al. (2007) concluded that A20 is a key protein involved in tamoxifen resistance.
Song et al. (2008) found that silencing of A20 allowed mouse dendritic cells (DCs) to hyperactivate cytotoxic lymphocytes and T-helper cells and inhibit regulatory T cells (Tregs), enhancing infiltration of tumor-infiltrating lymphocytes into tumors. They proposed that the inhibitory effects of A20-silenced DCs on Tregs may tip the balance from immune suppression to antitumor immunity.
Shembade et al. (2010) showed that A20 inhibits the E3 ligase activities of TRAF6 (602355), TRAF2 (601895), and cIAP1 (601712) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C (602963). A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways.
By immunoblot analysis, Coornaert et al. (2008) showed that MALT1 (604860) is a functional cysteine protease activated by T cell receptor stimulation and that it rapidly cleaves A20 after arg439, impairing its NFKB (see 164011) inhibitor function. Coornaert et al. (2008) concluded that A20 is a substrate of MALT1 and that MALT1 proteolytic activity is important in the fine tuning of T cell antigen receptor signaling.
Using immunoprecipitation, immunoblot, and FACS analysis, Ferch et al. (2009) showed that aggressive activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) cells, but not germinal center B cell-like (GCB) DLBCL, possess constitutively assembled CARD11 (607210)-BCL10 (603517)-MALT1 (CBM) complexes that continuously and selectively process A20. Inhibition of MALT1 blocks A20 and BCL10 cleavage, reduces NFKB activity, and decreases the expression of NFKB targets BCLXL (BCL2L1; 600039), IL6 (147620), and IL10 (124092). Inhibition of MALT1 paracaspase leads to ABC-DLBCL cell death and growth retardation. Ferch et al. (2009) concluded that MALT1 paracaspase activity has a growth-promoting role, specifically in ABC-DLBCL cells, and proposed that MALT1 protease activity is a potential target for pharmacologic treatment of ABC-DLBCL.
Ma et al. (2014) observed that myeloid DCs (mDCs) isolated from patients chronically infected with hepatitis C virus (HCV; see 609532) expressed significantly higher A20 than did mDCs from healthy individuals or from individuals who had achieved sustained virologic responses (SVRs) following antiviral treatment with IFNA (147660). A20 expression in mDCs from HCV-infected patients undergoing IFNA treatment was lower than in untreated patients, SVR patients, or healthy individuals. Stimulation of mDCs with polyI:C showed differences in A20 expression between HCV patients and healthy individuals, but the differences could be abrogated by IFNA treatment in vitro. Expression of A20 by polyI:C-activated mDCs negatively correlated with expression of HLA-DRA (142860), CD86 (601020), and CCR7 (600242), as well as with secretion of IL12 (161560). A20 expression positively correlated with IL10 production. Silencing of A20 increased IL12 production in mDCs of patients chronically infected with HCV. Ma et al. (2014) proposed that A20 plays a crucial role in the negative regulation of innate immune responses during chronic viral infection.
Using genetically engineered mice bearing mutations in the A20 ovarian tumor-type deubiquitinase (OTU) domain or in the zinc finger-4 (Znf4) ubiquitin-binding motif, Wertz et al. (2015) investigated paradoxical in vitro and in vivo findings regarding the role of A20 in attenuating inflammatory signaling. Wertz et al. (2015) found that phosphorylation of A20 promotes cleavage of lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumor necrosis factor (TNF; 191160). Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 (191190) signaling complex by blocking A20-mediated disassembly of lys63-linked polyubiquitin scaffolds. Wertz et al. (2015) concluded that collectively the studies revealed molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.
Somatic Mutations
Using a genomewide analysis of genetic lesions in 238 B cell lymphomas, Kato et al. (2009) showed that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (see 604860) (18 of 87; 21.8%) and Hodgkin lymphoma (see 236000) of the nodular sclerosis histology (5 of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When reexpressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappa-B activation. The A20-deficient cells stably generated tumors in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by reexpression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa-B activity due to reexpression of A20 depended, at least partly, on cell surface receptor signaling, including the tumor necrosis factor receptor (TNFR; see 191190). Considering the physiologic function of A20 in the negative modulation of NF-kappa-B activation induced by multiple upstream stimuli, Kato et al. (2009) concluded that signaling of NF-kappa-B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.
Compagno et al. (2009) showed that greater than 50% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) and a smaller fraction of germinal center B cell-like (GCB)-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3) and positive regulators of NF-kappa-B (see 164011). Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Compagno et al. (2009) concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses.
Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (CHL), are dependent on constitutive activation of NFKB. By sequencing TNFAIP3 in CHL cell lines and in laser-microdissected HRS cells from CHL biopsies, Schmitz et al. (2009) identified somatic mutations in 16 of 36 CHL cases. The changes, which were usually biallelic, were found in 2 Epstein-Barr virus (EBV)-positive CHLs and in 14 EBV-negative CHLs. Reconstitution of wildtype TNFAIP3 in TNFAIP3-deficient CHL cell lines resulted in a significant decrease in transcripts of selected NFKB target genes and caused cytotoxicity. TNFAIP3 mutations were also found in 5 of 14 cases of primary mediastinal B-cell lymphoma (PMBL), another lymphoma marked by constitutive NFKB activity. Schmitz et al. (2009) concluded that TNFAIP3 is a key regulator of NFKB activity and suggested that TNFAIP3 is a novel tumor suppressor gene in CHL and PMBL. They stressed that the clustering of destructive mutations in EBV-negative CHL cases may indicate that TNFAIP3 inactivation and EBV infection/transformation may be complementing functions in CHL pathogenesis.
Braggio et al. (2009) identified biallelic inactivation of TNF receptor-associated factor-3 (TRAF3; 601896) in 3 (5.3%) of 57 Waldenstrom macroglobulinemia (WM; see 153600) samples. TRAF3 inactivation was associated with transcriptional activation of NF-kappa-B. In addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to the development of WM. The results indicated that mutational activation of the NF-kappa-B pathway plays a role in the pathogenesis of WM.
Familial Behcet-Like Autoinflammatory Syndrome 1
In affected members of 6 unrelated families with familial Behcet-like autoinflammatory syndrome (AIFBL1; 616744), Zhou et al. (2016) identified 6 different heterozygous truncating mutations in the TNFAIP3 gene (191163.0001-191163.0006). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; 3 subsequent mutations were found in 3 of 150 probands with a similar disorder who were directly screened for TNFAIP3 mutations. The sixth mutation was found in 1 of 768 individuals diagnosed with Behcet disease (109650) who underwent targeted sequencing. In vitro functional cellular expression studies showed that all mutations failed to suppress TNF-induced NFKB (see 164011) activity, although not in a dominant-negative fashion, which suggested haploinsufficiency as a disease mechanism. Patient cells showed reduced recruitment of TNFAIP3 to the TNFR complex (see 191190) compared to control cells. Patient-derived cells showed increased phosphorylation of IKKA (600664) and IKKB (603258) and subsequent degradation of I-kappa-B-alpha (NFKBIA; 164008), with nuclear translocation of the NFKB p65 subunit (RELA; 164014) together with increased expression of NFKB-mediated proinflammatory cytokines, consistent with activation of the NFKB pathway. Cells expressing the mutant proteins showed defective removal of lys63-linked ubiquitin from TRAF6 (602355), NEMO (IKBKG; 300248), and RIP1 (603453) after stimulation with TNF, indicating inefficient deubiquitination. Levels of proinflammatory cytokines were substantially higher in patient serum compared to controls, and showed evidence of increased IL1B (147720) signaling.
In 22 affected individuals from 9 unrelated Japanese families with AIFBL, Kadowaki et al. (2018) identified heterozygous mutations in the TNFAIP3 gene (see, e.g., 191163.0007). There were 5 frameshift mutations, 2 splice site mutation, 1 nonsense mutation, and 1 missense variant, suggesting haploinsufficiency as the pathogenetic mechanism. Western blot analysis of cells carrying the mutations showed that the nonsense and frameshift mutations, but not the C243Y missense variant, caused decreased protein levels compared to controls. In vitro functional expression assays using a luciferase reporter showed that the nonsense and frameshift mutations, but not the C243Y missense variant, resulted in increased NFKB gene activity compared to wildtype, consistent with defective TNFAIP3 function. The authors postulated haploinsufficiency of A20 as the pathogenetic disease mechanism.
In a 13-year-old Chinese boy with AIFBL, Dong et al. (2019) identified a heterozygous missense variant in the TNFAIP3 gene (M476I; 191163.0008). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (164011) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (191160) compared to controls, consistent with the phenotype of autoinflammation.
In a 27-year-old man of Ashkenazi Jewish descent with AIFBL, Gans et al. (2020) identified a heterozygous frameshift mutation in the TNFAIP3 gene (191163.0009). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Familial segregation studies and functional studies of the variant were not performed, but it was predicted to cause haploinsufficiency of TNFAIP3. In addition to autoinflammation and autoimmunity, the patient had features of a primary combined immunodeficiency, thus expanding the phenotype associated with TNFAIP3 mutations.
Associations Pending Confirmation
For discussion of a possible association between systemic lupus erythematosus and variation in the TNFAIP3 gene, see 612378.
Lee et al. (2000) generated A20-deficient mice by targeted disruption. A20 +/- mice appeared normal without evidence of pathology. A20 -/- mice, born from interbred A20 +/- mice in mendelian ratios, developed runting as early as 1 week of age. Mice deficient for A20 developed severe inflammation and cachexia, were hypersensitive to both lipopolysaccharide and TNF (191160), and died prematurely. A20-deficient cells failed to terminate TNF-induced NFKB (see 164011) responses. These cells were also more susceptible than control cells to undergo TNF-mediated program cell death. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NFKB responses in vivo.
Using mice doubly deficient in either A20 and Tnf or A20 and Tnfr1 (191190), Boone et al. (2004) showed that, in addition to terminating TNF-induced signals, A20 is required for terminating TLR (e.g., TLR4, 603030)-induced activity of NFKB. Mutation and immunoblot analyses indicated that A20 acts, via its conserved OTU-like domain, as a deubiquitinating enzyme on ubiquitinated TRAF6 (602355).
In mice subjected to aortic banding, Cook et al. (2003) detected greater than 4-fold A20 upregulation (p less than 0.05) at 3 hours, coinciding with peak NFKB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (EDN1; 131240) (2.8-fold and 4-fold, respectively; p less than 0.05), again paralleling NFKB activation. Cardiomyocytes infected with an adenoviral vector (Ad) encoding A20 inhibited TNF-stimulated NFKB signaling with an efficacy comparable to dominant-negative inhibitor of kappa-B kinase-beta (IKBKB; 603258). Ad-IKBKB-infected cardiomyocytes exhibited increased apoptosis when serum-starved or subjected to hypoxia-reoxygenation, whereas Ad-A20-infected cardiomyocytes did not. Expression of Ad-A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1 (131240). Cook et al. (2003) concluded that A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NFKB signaling without sensitizing cardiomyocytes to apoptosis.
Wolfrum et al. (2007) found that ApoE (107741) -/- mice that were haploinsufficient for A20 developed larger atherosclerotic lesions than ApoE -/- mice with normal A20 expression. The larger lesions were associated with increased expression of the NF-kappa-B target genes Vcam1 (192225), Icam1 (147840), and Mcsf (CSF1; 120420) and increased plasma levels of NF-kappa-B-regulated cytokines. In contrast, overexpression of A20 resulted in smaller lesions. Wolfrum et al. (2007) concluded that A20, acting mainly through NF-kappa-B, influences atherosclerosis susceptibility.
Matmati et al. (2011) showed that specific ablation of TNFAIP3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis (180300). Myeloid-A20-deficient mice had high levels of inflammatory cytokines in their serum, consistent with a sustained NF-kappa-B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 (602170) and IL6 (147620)-dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Matmati et al. (2011) concluded that, taken together, their observations revealed a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis.
Lu et al. (2013) generated 2 lines of gene-targeted mice by abrogating either the deubiquitinating activity of A20 (Tnfaip3-OTU mice) or zinc finger-4 of A20 (Tnfaip3-ZF4 mice). Both strains exhibited increased responses to Tnf and sensitivity to colitis. The deubiquitinating motif restricted both lys48- and lys63-linked ubiquitination of Rip1. ZF4 was required for recruitment of A20 to ubiquitinated Rip1. The 2 mutant A20 proteins complemented each other through dimerization to regulate Rip1 ubiquitination and Nfkb signaling in compound mutant Tnfaip3-OTU/Tnfaip3-ZF4 cells. Lu et al. (2013) concluded that A20 proteins collaborate to restrict TNF signaling.
Vande Walle et al. (2014) showed that rheumatoid arthritis in A20 myeloid cell-specific knockout mice (A20(myel-KO); Matmati et al., 2011) relies on the Nlrp3 inflammasome and Il1 receptor (IL1R; 147810) signaling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and pro-Il1b (147720). As a result, A20 deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 (CASP1; 147678) activation, pyroptosis, and Il1B secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 (606831) and Aim2 (604578) inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, since deletion of Nlrp3, Casp1, and the Il1 receptor markedly protects against rheumatoid arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. Vande Walle et al. (2014) concluded that these results revealed A20 as a novel negative regulator of NLRP3 inflammasome activation, and described A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS; see 126200). In both EAE and MS, autoreactive T cells infiltrate the central nervous system (CNS) and mediate an inflammatory response that causes demyelination and axon degradation. Liu et al. (2014) found that expression of A20 was downregulated in EAE and in primary mouse astrocytes stimulated with IL17 (see 603149). Expression profiling revealed that expression of microRNA-873 (MIR873; 616137) was upregulated in EAE and activated astrocytes. Liu et al. (2014) identified an Mir873 target sequence in the 3-prime UTR of an A20 transcript. Overexpression and reporter gene assays revealed that Mir873 facilitated production of inflammatory cytokines and chemokines in astrocytes stimulated with IL17 by directly downregulating expression of A20 and indirectly promoting NF-kappa-B (see NFKB1, 164011) activation. Use of an miRNA sponge that lowered Mir873 content reduced production of cytokines in activated astrocytes and ameliorated CNS damage in EAE mice. Silencing of A20 exacerbated the effect of Mir873 in activated astrocytes and increased demyelination in EAE mice. Liu et al. (2014) concluded that upregulation of MIR873 and downregulation of A20 contribute to inflammatory damage in MS.
In 3 affected members of a European Canadian family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.680T-A transversion (c.680T-A, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a leu227-to-ter (L227X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In 3 affected members of a European American family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous 1-bp deletion (c.671delT, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Phe224SerfsTer4) in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In a Turkish father and son with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.811C-T transition (c.811C-T, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in an arg271-to-ter (R271X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In a woman with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a de novo heterozygous 1-bp deletion (c.1809delG, NM_006290.2) in exon 7 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Thr604ArgfsTer93) in the ZnF4 domain, which is essential for ubiquitin ligase activity and dimerization. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In a Dutch mother and daughter with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.918C-G transversion (c.918C-G, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in a tyr306-to-ter (Y306X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In a Turkish mother and her 2 daughters with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous 1-bp deletion (c.799delG, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Pro268LeufsTer19) in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells.
In a mother and daughter (P18 and P17) from a Japanese family (family 6) with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Kadowaki et al. (2018) identified a heterozygous 1-bp deletion (c.1345delA) in the TNFAIP3 gene, resulting in a frameshift and premature termination (Asn449ThrfsTer28). Western blot analysis of cells with the mutation showed mildly decreased TNFAIP3 protein levels compared to wildtype. In vitro functional expression assays in HEK293 cells using a luciferase reporter showed that the mutation resulted in increased NFKB (164011) gene activity compared to wildtype, consistent with defective TNFAIP3 function. P17 was a 7-year-old girl with periodic fevers and aphthous stomatitis since infancy. She also had a developmental disorder. Her mother had stomatitis from childhood, abdominal pain and fever since the teenage years, and genital ulcers, resulting in a diagnosis of Behcet disease. Three additional maternal family members who were not genotyped had Behcet-like symptoms, consistent with autosomal dominant inheritance.
In a 13-year-old Chinese boy with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Dong et al. (2019) identified a heterozygous c.1428G-A transition in the TNFAIP3 gene, resulting in a met476-to-ile (M476I) substitution in the zinc finger 2 domain (ZF2). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (164011) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (191160) compared to controls, consistent with the phenotype of autoinflammation. The patient presented with a history of recurrent fever, lymphadenopathy, skin rash, arthritis, and multiple recurrent oral and gastrointestinal ulcerations. He also had recurrent tonsillitis, persistent EBV viremia, and variable lymphocyte abnormalities.
In a 27-year-old man of Ashkenazi Jewish descent with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Gans et al. (2020) identified a heterozygous 1-bp deletion (c.912del, NM_001270507) in exon 6 of the TNFAIP2 gene, predicted to result in a frameshift and premature termination (Glu305SerfsTer3). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Functional studies of the variant were not performed, but it was consistent with haploinsufficiency of TNFAIP3. The patient had recurrent fevers, mouth ulcers, and chronic diarrhea since childhood, consistent with autoinflammation and autoimmunity, but he also had recurrent infections and EBV viremia, suggesting a primary immunodeficiency. Laboratory studies showed hypogammaglobulinemia, low B, T, and NK cells, and impaired T-cell proliferation. There were increased serum levels of inflammatory markers and activation of the NFKB (see 164011) signaling pathway with increased expression of interferon response genes. This case report expanded the immune dysregulation phenotype associated with TNFAIP3 mutations to include combined immunodeficiency.
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