%0 Journal Article
%A Uggenti, Carolina
%A Lepelley, Alice
%A Depp, Marine
%A Badrock, Andrew P
%A Rodero, Mathieu P
%A El-Daher, Marie-Thérèse
%A Rice, Gillian I
%A Dhir, Somdutta
%A Wheeler, Ann P
%A Dhir, Ashish
%A Albawardi, Waad
%A Frémond, Marie-Louise
%A Seabra, Luis
%A Doig, Jennifer
%A Blair, Natalie
%A Martin-Niclos, Maria José
%A Della Mina, Erika
%A Rubio-Roldán, Alejandro
%A García-Pérez, Jose L
%A Sproul, Duncan
%A Rehwinkel, Jan
%A Hertzog, Jonny
%A Boland-Auge, Anne
%A Olaso, Robert
%A Deleuze, Jean-François
%A Baruteau, Julien
%A Brochard, Karine
%A Buckley, Jonathan
%A Cavallera, Vanessa
%A Cereda, Cristina
%A De Waele, Liesbeth M H
%A Dobbie, Angus
%A Doummar, Diane
%A Elmslie, Frances
%A Koch-Hogrebe, Margarete
%A Kumar, Ram
%A Lamb, Kate
%A Livingston, John H
%A Majumdar, Anirban
%A Lorenço, Charles Marques
%A Orcesi, Simona
%A Peudenier, Sylviane
%A Rostasy, Kevin
%A Salmon, Caroline A
%A Scott, Christiaan
%A Tonduti, Davide
%A Touati, Guy
%A Valente, Marialuisa
%A van der Linden, Hélio
%A Van Esch, Hilde
%A Vermelle, Marie
%A Webb, Kate
%A Jackson, Andrew P
%A Reijns, Martin A M
%A Gilbert, Nick
%A Crow, Yanick J
%T cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
%D 2020
%U http://hdl.handle.net/10668/16658
%X Inappropriate 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.
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