The most common human ADAR1p150 Zα domain mutation P193A is well tolerated in mice

Summary 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, broadly 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. We report the development of an independent murine P195A knock-in mouse, homologous to the human P193A mutation. The Adar1P195A/P195Amice are largely normal and the mutation is well tolerated. Contrasting with previous reports when the P195A mutation was compounded with an ADAR1 null allele, the majority of mice have only a modest reduction in weaning weight and survived long-term. Severe runting and shortened survival of Adar1P195A/-animals are dependent on the parental genotype. The P195A mutation is well tolerated in vivo and the loss of MDA5 is sufficient to completely rescue the Adar1P195A/- mice.