Uggenti, CarolinaLepelley, AliceDepp, MarineBadrock, Andrew PRodero, Mathieu PEl-Daher, Marie-ThérèseRice, Gillian IDhir, SomduttaWheeler, Ann PDhir, AshishAlbawardi, WaadFrémond, Marie-LouiseSeabra, LuisDoig, JenniferBlair, NatalieMartin-Niclos, Maria JoséDella Mina, ErikaRubio-Roldán, AlejandroGarcía-Pérez, Jose LSproul, DuncanRehwinkel, JanHertzog, JonnyBoland-Auge, AnneOlaso, RobertDeleuze, Jean-FrançoisBaruteau, JulienBrochard, KarineBuckley, JonathanCavallera, VanessaCereda, CristinaDe Waele, Liesbeth M HDobbie, AngusDoummar, DianeElmslie, FrancesKoch-Hogrebe, MargareteKumar, RamLamb, KateLivingston, John HMajumdar, AnirbanLorenço, Charles MarquesOrcesi, SimonaPeudenier, SylvianeRostasy, KevinSalmon, Caroline AScott, ChristiaanTonduti, DavideTouati, GuyValente, Marialuisavan der Linden, HélioVan Esch, HildeVermelle, MarieWebb, KateJackson, Andrew PReijns, Martin A MGilbert, NickCrow, Yanick J2023-02-092023-02-092020-11-23http://hdl.handle.net/10668/16658Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.enAutoimmune Diseases of the Nervous SystemCell LineChromatinDNAGene Expression RegulationHCT116 CellsHEK293 CellsHereditary Autoinflammatory DiseasesHistonesHumansInterferon Type IMembrane ProteinsNervous System MalformationsNucleotides, CyclicNucleotidyltransferasesRNA PrecursorsRNA-Binding ProteinsRibonucleoprotein, U7 Small Nuclearresearch article33230297open access10.1038/s41588-020-00737-31546-1718https://discovery.ucl.ac.uk/10117723/3/Baruteau_AGS8-9%20main_NG%20resubmission_v4.pdf