{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:59:01Z","timestamp":1788785941994,"version":"build-2803163510"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":208,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Heterozygous loss-of-function mutations in the TNFAIP3 gene lead to A20 haploinsufficiency (HA20). A20 protein is a negative feedback regulator of NF-\u03baB signaling. Traditionally, HA20 is associated with Beh\u00e7et's disease-like symptoms, however, recent findings suggest it may also manifest with a broader array of autoimmune diseases. Here, we describe a novel TNFAIP3 variant in a Dutch family, predominantly presenting with polyautoimmunity rather than autoinflammatory manifestations. We evaluated two patients from a Dutch family with autoimmune symptoms. Whole-exome sequencing (WES) identified a heterozygous c.608T&amp;gt;G (p.Leu203Arg) missense variant in TNFAIP3, located within the OTU domain. Functional analyses included immunoblotting of peripheral blood mononuclear cells (PBMCs) and an overexpression model using transfected HEK293T cells. A20 protein expression was evaluated, while phosphoflow cytometry assessed phosphorylation of key signaling molecules in the NF-\u03baB, STAT and mTOR pathways. Inflammatory cytokine production was measured in cell culture supernatants. Overexpression of this missense A20 variant in HEK293T enhanced NF-\u03baB signaling, reflected by increased TRAF6 expression and I\u03baB\u03b1 phosphorylation. Patient-derived PBMCs demonstrated reduced A20 expression, increased phosphorylation within the NF-\u03baB, STAT1, and mTOR pathways, and elevated production of pro-inflammatory cytokines. These molecular alterations suggest disrupted immune regulation contributing to the observed autoimmune phenotype. The identification of this novel TNFAIP3 variant contributing to HA20 expands the clinical spectrum to include predominant autoimmune manifestations. In addition to NF-\u03baB and STAT1 activation, we discovered mTOR pathway activation, shedding new light on A20\u2019s function and progression toward autoimmunity. Furthermore, the involvement of mTOR pathway also provides new therapeutic possibilities.<\/jats:p>","DOI":"10.1093\/cei\/uxaf048","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:06:15Z","timestamp":1752501975000},"source":"Crossref","is-referenced-by-count":3,"title":["A novel missense variant in TNFAIP3 associated with autoimmunity reveals the contribution of STAT1\/mTOR pathways"],"prefix":"10.1093","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9730-9298","authenticated-orcid":false,"given":"Judith","family":"Potjewijd","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Immunology, Maastricht University Medical Center , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J P M","family":"Koenen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caspar I","family":"van der Made","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen ,","place":["the Netherlands"]},{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center and Radboud Institute for Molecular Life Sciences , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"van Rijssen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehui","family":"He","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center , Nijmegen ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Ysermans","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Immunology, Maastricht University Medical Center , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liset","family":"Ungethum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud","family":"Theunissen","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Immunology, Maastricht University Medical Center , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon J","family":"Schurgers","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-6985","authenticated-orcid":false,"given":"Jan","family":"Damoiseaux","sequence":"additional","affiliation":[{"name":"Central Diagnostic Laboratory, Maastricht University Medical Center , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"van Paassen","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Immunology, Maastricht University Medical Center , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben L","family":"Smeets","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center , Nijmegen ,","place":["the Netherlands"]},{"name":"Department of Laboratory Medicine, Radboudumc Laboratory for Diagnostics, Radboud University Medical Center , Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"2025092405571095000_CIT0001","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/ng.3459","article-title":"Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease","volume":"48","author":"Zhou","year":"2016","journal-title":"Nat 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