{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:15:44Z","timestamp":1793646944168,"version":"4.5.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Aicardi-Gouti\u00e8res syndrome (AGS) is a rare monogenic type I interferonopathy characterized by dysregulated inflammation and tissue damage that primarily affects the central nervous system. AGS is genetically diverse, with pathogenic variants across multiple genes, including TREX1, which drives excessive type I interferon (IFN) production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study investigated the genetic and molecular mechanisms underlying AGS in a family of two affected children, focusing on the role of <jats:italic>TREX1<\/jats:italic> variants in protein expression and dysregulation of the interferon pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genomic sequencing data were used to identify <jats:italic>TREX1<\/jats:italic> variants in the affected children. Functional assays in patient-derived lymphoblastoid cells (LCLs) and cell line models were used to evaluate TREX1 expression and activation of the cGAS-STING pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two homozygous <jats:italic>TREX1<\/jats:italic> variants were identified in two affected children. Functional analyses showed that both variants are required to mirror the near-absent protein levels observed in LCL and to cause excessive activation of IRF3 in cGAS-STING pathway in response to cytosolic DNA stimulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>To our knowledge, our findings demonstrate, for the first time, the compound effect of two rare homozygous variants account for AGS. This also reiterates the importance of molecular and functional assessments of genomic variants identified by sequencing.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1557632","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T06:39:33Z","timestamp":1740119973000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Two rare mutations in homozygosity synergize to silence TREX1 in Aicardi-Gouti\u00e8res syndrome"],"prefix":"10.3389","volume":"16","author":[{"given":"Tamar","family":"Rubin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Bernier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily Siok","family":"Hoon Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Salman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziz","family":"Mhanni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Marles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Angers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald C.","family":"Vinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Roussel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0500-x","article-title":"Type I interferonopathies\u2013an expanding disease spectrum of immunodysregulation","volume":"37","author":"Lee-Kirsch","year":"2015","journal-title":"Semin Immunopathol"},{"key":"B2","article-title":"Aicardi-Gouti\u00e8res syndrome: differential diagnosis and etiopathogenesis","volume":"18","author":"Lanzi","year":"2003","journal-title":"Funct Neurol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70258-8","article-title":"Assessment of interferon-related biomarkers in Aicardi-Gouti\u00e8res syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study","volume":"12","author":"Rice","year":"2013","journal-title":"Lancet Neurol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1086\/521373","article-title":"Clinical and molecular phenotype of Aicardi-Goutieres syndrome","volume":"81","author":"Rice","year":"2007","journal-title":"Am J Hum Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.3.183","article-title":"Cree encephalitis is allelic with Aicardi-Gouti\u00e9res syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism","volume":"40","author":"Crow","year":"2003","journal-title":"J Med Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00737-3","article-title":"cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing","volume":"52","author":"Uggenti","year":"2020","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e13314","DOI":"10.1111\/sji.13314","article-title":"Aicardi-Gouti\u00e8res syndrome: A monogenic type I interferonopathy","volume":"98","author":"Liu","year":"2023","journal-title":"Scand J Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-022-00679-2","article-title":"Clinical spectrum and currently available treatment of type I interferonopathy Aicardi\u2013Gouti\u00e8res syndrome","volume":"19","author":"Dell\u2019Isola","year":"2023","journal-title":"World J Pediatr"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ng2091","article-title":"Mutations in the gene encoding the 3\u2019-5\u2019 DNA exonuclease TREX1 are associated with systemic lupus erythematosus","volume":"39","author":"Lee-Kirsch","year":"2007","journal-title":"Nat Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ng2082","article-title":"C-terminal truncations in human 3\u2019-5\u2019 DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy","volume":"39","author":"Richards","year":"2007","journal-title":"Nat Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1086\/513443","article-title":"Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant aicardi-gouti\u00e8res syndrome","volume":"80","author":"Rice","year":"2007","journal-title":"Am J Hum Genet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.15.6719-6727.2004","article-title":"Gene-targeted mice lacking the Trex1 (DNase III) 3\u2019\u2013>5\u2019 DNA exonuclease develop inflammatory myocarditis","volume":"24","author":"Morita","year":"2004","journal-title":"Mol Cell Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2174\/1381612825666190902113218","article-title":"TREX1 as a potential therapeutic target for autoimmune and inflammatory diseases","volume":"25","author":"Tao","year":"2019","journal-title":"Curr Pharm Des"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.28.19655","article-title":"Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3\u2019\u2013>5\u2019 exonucleases","volume":"274","author":"Mazur","year":"1999","journal-title":"J Biol Chem"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400737","article-title":"TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner","volume":"192","author":"Ablasser","year":"2014","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229963","article-title":"Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA","volume":"339","author":"Wu","year":"2013","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.05.009","article-title":"The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING","volume":"3","author":"Diner","year":"2013","journal-title":"Cell Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1516465112","article-title":"Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases","volume":"112","author":"Gao","year":"2015","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3558","article-title":"Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing","volume":"17","author":"Chen","year":"2016","journal-title":"Nat Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.06.032","article-title":"Trex1 prevents cell-intrinsic initiation of autoimmunity","volume":"134","author":"Stetson","year":"2008","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ebiom.2016.05.039","article-title":"Ligand-induced ordering of the C-terminal tail primes STING for phosphorylation by TBK1","volume":"9","author":"Tsuchiya","year":"2016","journal-title":"EBioMedicine"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1042\/BST0370535","article-title":"Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease","volume":"37","author":"Lindahl","year":"2009","journal-title":"Biochem Soc Trans"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.660184","article-title":"TREX1 as a novel immunotherapeutic target","volume":"12","author":"Hemphill","year":"2021","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0147-3","article-title":"Human disease phenotypes associated with mutations in TREX1","volume":"35","author":"Rice","year":"2015","journal-title":"J Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ng1845","article-title":"Mutations in the gene encoding the 3\u2019-5\u2019 DNA exonuclease TREX1 cause Aicardi-Gouti\u00e8res syndrome at the AGS1 locus","volume":"38","author":"Crow","year":"2006","journal-title":"Nat Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-016-0359-1","article-title":"Assessment of type I interferon signaling in pediatric inflammatory disease","volume":"37","author":"Rice","year":"2017","journal-title":"J Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e178456","DOI":"10.1172\/jci.insight.178456","article-title":"IFN-signaling gene expression as a diagnostic biomarker for monogenic interferonopathies","volume":"9","author":"Adang","year":"2024","journal-title":"JCI Insight"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e20212427","DOI":"10.1084\/jem.20212427","article-title":"Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic","volume":"219","author":"Duncan","year":"2022","journal-title":"J Exp Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1055\/s-0036-1582250","article-title":"Neurological involvement in tetrahydrobiopterin deficiency","volume":"6","author":"Mascaro","year":"2016","journal-title":"J Pediatr Biochem"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1557632\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T06:39:35Z","timestamp":1740119975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1557632\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,21]]},"references-count":29,"alternative-id":["10.3389\/fimmu.2025.1557632"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1557632","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,21]]},"article-number":"1557632"}}