The phenotype of the most common human ADAR1p150 Zα mutation P193A in mice is partially penetrant.

ADAR1 -mediated A-to-I RNA editing is a self-/non-self-discrimination mechanism for cellular double-stranded RNAs. ADAR mutations are one cause of Aicardi-Goutières Syndrome, an inherited paediatric encephalopathy, classed as a "Type I interferonopathy." The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform-specific Zα domain. Here, we report the development of an independent murine P195A knock-in mouse, homologous to human P193A. The Adar1 mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1 ), approximately half the animals are runted with a shortened lifespan while the remaining Adar1 animals are normal, contrasting with previous reports. The phenotype of the Adar1 animals is both associated with the parental genotype and partly non-genetic/environmental. Complementation with an editing-deficient ADAR1 (Adar1 ), or the loss of MDA5, rescues phenotypes in the Adar1 mice.