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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 publication




Journal article


Nature genetics

Publication Date





1364 - 1372


Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.


Cell Line, HCT116 Cells, Chromatin, Humans, Autoimmune Diseases of the Nervous System, Nervous System Malformations, Nucleotidyltransferases, RNA-Binding Proteins, Ribonucleoprotein, U7 Small Nuclear, Interferon Type I, Membrane Proteins, Histones, RNA Precursors, DNA, Nucleotides, Cyclic, Gene Expression Regulation, Hereditary Autoinflammatory Diseases, HEK293 Cells