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. Synopsis Using murine models of the ADAR1 p.P193A mutation found in Aicardi‐Goutières Syndrome patients shows that MDA5 is the primary mediator of the phenotypes observed. RNA editing‐independent functions of ADAR1, parental genotype, and non‐genetic factors contribute to the severity/penetrance of phenotypes in Adar1P195A/− mice. The P195A mutation has a limited effect on RNA editing. Compound P195A mutation Adar1P195A/− mice show partially penetrant runting and shortened lifespan. Knockout of MDA5 or re‐expression of editing‐deficient ADAR1 can rescue the phenotypes of runted Adar1P195A/− mice. Graphical Abstract Using murine models of the ADAR1 p.P193A mutation found in Aicardi‐Goutières Syndrome patients shows that MDA5 is the primary mediator of the phenotypes observed. RNA editing‐independent functions of ADAR1, parental genotype, and non‐genetic factors contribute to the severity/penetrance of phenotypes in Adar1P195A/− mice.