Chronic activation of type I interferon (IFN-I) signaling related severe diseases, including Aicardi–Goutières syndrome and bilateral striatal necrosis, is driven by the RNA deaminase ADAR1 mutations; moreover Z-RNA contains an alternative left-handed double-helix structure recognized by the Zα domain of IFN-induced ADAR1, the p150 isoform. Here, ADAR is linked to Aicardi-Goutieres syndrome.