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Review
. 2024 Jul 29;25(15):8275.
doi: 10.3390/ijms25158275.

Genetic Mutations Associated With TNFAIP3 (A20) Haploinsufficiency and Their Impact on Inflammatory Diseases

Eva Bagyinszky  1 , Seong Soo A An  2
Affiliations
Review

Genetic Mutations Associated With TNFAIP3 (A20) Haploinsufficiency and Their Impact on Inflammatory Diseases

Eva Bagyinszky et al. Int J Mol Sci. .

Abstract

TNF-α-induced protein 3 (TNFAIP3), commonly referred to as A20, is an integral part of the ubiquitin-editing complex that significantly influences immune regulation, apoptosis, and the initiation of diverse immune responses. The A20 protein is characterized by an N-terminal ovarian tumor (OTU) domain and a series of seven zinc finger (ZNF) domains. Mutations in the TNFAIP3 gene are implicated in various immune-related diseases, such as Behçet's disease, polyarticular juvenile idiopathic arthritis, autoimmune thyroiditis, autoimmune hepatitis, and rheumatoid arthritis. These mutations can lead to a spectrum of symptoms, including, but not limited to, recurrent fever, ulcers, rashes, musculoskeletal and gastrointestinal dysfunctions, cardiovascular issues, and respiratory infections. The majority of these mutations are either nonsense (STOP codon) or frameshift mutations, which are typically associated with immune dysfunctions. Nonetheless, missense mutations have also been identified as contributors to these conditions. These genetic alterations may interfere with several biological pathways, notably abnormal NF-κB signaling and dysregulated ubiquitination. Currently, there is no definitive treatment for A20 haploinsufficiency; however, therapeutic strategies can alleviate the symptoms in patients. This review delves into the mutations reported in the TNFAIP3 gene, the clinical progression in affected individuals, potential disease mechanisms, and a brief overview of the available pharmacological interventions for A20 haploinsufficiency. Mandatory genetic testing of the TNFAIP3 gene should be performed in patients diagnosed with autoinflammatory disorders to better understand the genetic underpinnings and guide treatment decisions.

Keywords: A20 haploinsufficiency; TNFAIP3 gene; autoimmunity; haploinsufficiency; immune dysfunctions; mutations; therapy.

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Conflict of interest statement

There is no conflict of interest.

Figures

Figure 1
Figure 1
Functions of TNFAIP3 (A20) protein [1,2,3,4,5,6]. The 3D structure of the A20 protein was generated using the Alphafold Colab v1.5.5 tool [7] (https://colab.research.google.com/github/sokrypton/ColabFold/blob/main/AlphaFold2.ipynb, accessed 10 June 2024). Figure was made using the BioRender tool.
Figure 2
Figure 2
Frameshift and STOP codon mutations in TNFAIP3 gene.
Figure 3
Figure 3
Missense mutations in TNFAIP3 gene.
Figure 4
Figure 4
Roles of A20 protein in NfkappaB signaling [61,62,63]. The 3D structure of the A20 protein was generated using Alphafold Colab v1.5.5 tool (https://colab.research.google.com/github/sokrypton/ColabFold/blob/main/AlphaFold2.ipynb, accessed on 10 June 2024) [7]. Figure was made using BioRender tool.
Figure 5
Figure 5
Possible pathways affected by TNFAIP3 mutations associated with atypical phenotypes. Figure was made using BioRender Tool.
See this image and copyright information in PMC

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This researchwas supported by National Research Foundation of Korea: 2021R1A6A1A03038996 and Ministry of Education Korea: RS-2023-00251396.

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