ArticleArthritis research & therapy2021
Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.
Article in Arthritis research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 24 citations in OpenAlex.
- The ubiquitin-editing enzyme A20 (TNFAIP3): mechanisms of activation, biological function, diseases and therapeutic targets.Molecular biomedicine · 2026Review
- Limitations of EBV transformed human Raji B cells as a model for measuring canonical NF-κB activation.bioRxiv : the preprint server for biology · 2026Article
- Identification of genetic variants in B cell expressed genes associated with systemic lupus erythematosus in African American females.ImmunoHorizons · 2026Article
- How I Treat: Haploinsufficiency of A20.Journal of human immunity · 2026Review
- Five children with haploinsufficiency of A20 caused by heterozygous mutations in theFrontiers in immunology · 2026Article
- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- Co-Occurrence ofInternational journal of molecular sciences · 2025Article
- Characterization of Genetic Landscape and Novel Inflammatory Biomarkers in Patients With Adult-Onset Still's Disease.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling.European journal of immunology · 2024Article
- Genetic Mutations Associated With TNFAIP3 (A20) Haploinsufficiency and Their Impact on Inflammatory Diseases.International journal of molecular sciences · 2024Review
- The Complexity of Being A20: From Biological Functions to Genetic Associations.Journal of clinical immunology · 2024Review
- Case report: Adult case of A20 haploinsufficiency suspected as neuro-Behçet disease.Frontiers in immunology · 2024Article
- Cellular models in autoinflammatory disease research.Clinical & translational immunology · 2024Review
- A critical region of A20 unveiled by missenseeLife · 2023Article
- The Expanding Spectrum of Autoinflammatory Diseases.Internal medicine (Tokyo, Japan) · 2023Article
- A20 Haploinsufficiency in East Asia.Frontiers in immunology · 2021Review
- Endocrinopathies in Inborn Errors of Immunity.Frontiers in immunology · 2021Review
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Authors and funding
10 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundA20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20.
methodsWe obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated.
resultsThe inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study.
conclusionsAmong the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.
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