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 P195A/P195A mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1 P195A/- ), approximately half the animals are runted with a shortened lifespan while the remaining Adar1 P195A/- animals are normal, contrasting with previous reports. The phenotype of the Adar1 P195A/- animals is both associated with the parental genotype and partly non-genetic/environmental. Complementation with an editing-deficient ADAR1 (Adar1 P195A/E861A ), or the loss of MDA5, rescues phenotypes in the Adar1 P195A/- mice.