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The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.

Original publication




Journal article


Cell reports

Publication Date





1482 - 1494


MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.


Liver, Fibroblasts, Animals, Mice, Inbred C57BL, Humans, Autoimmune Diseases of the Nervous System, Nervous System Malformations, Embryo Loss, Uracil, Adenosine Deaminase, Adaptor Proteins, Signal Transducing, RNA-Binding Proteins, Receptors, Interferon, RNA, Double-Stranded, Inosine, Inflammation Mediators, Cytokines, Survival Analysis, Crosses, Genetic, Transcription, Genetic, RNA Editing, Phenotype, Mutation, Female, Male, Tumor Suppressor Protein p53, Embryo, Mammalian, Immunity, Innate