cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Carolina Uggenti, Alice Lepelley, Marine Depp, Andrew P Badrock, Mathieu P Rodero, Marie-Thérèse El-Daher, Gillian I Rice, Somdutta Dhir, Ann P Wheeler, Ashish Dhir, Waad Albawardi, Marie-Louise Frémond, Luis Seabra, Jennifer Doig, Natalie Blair, Maria José Martin-Niclos, Erika Della Mina, Alejandro Rubio-Roldán, Jose L García-Pérez, Duncan SproulJan Rehwinkel, Jonny Hertzog, Anne Boland-Auge, Robert Olaso, Jean-François Deleuze, Julien Baruteau, Karine Brochard, Jonathan Buckley, Vanessa Cavallera, Cristina Cereda, Liesbeth M H De Waele, Angus Dobbie, Diane Doummar, Frances Elmslie, Margarete Koch-Hogrebe, Ram Kumar, Kate Lamb, John H Livingston, Anirban Majumdar, Charles Marques Lorenço, Simona Orcesi, Sylviane Peudenier, Kevin Rostasy, Caroline A Salmon, Christiaan Scott, Davide Tonduti, Guy Touati, Marialuisa Valente, Hélio van der Linden, Hilde Van Esch

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1364-1372
Number of pages13
JournalNature Genetics
Volume 52
Issue number12
Early online dateNov 23 2020
Publication statusPublished - Dec 2020


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