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

Abstract

AbstractADAR1 ‐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 Adar1P195A/P195A mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1P195A/−), approximately half the animals are runted with a shortened lifespan while the remaining Adar1P195A/− animals are normal, contrasting with previous reports. The phenotype of the Adar1P195A/− animals is both associated with the parental genotype and partly non‐genetic/environmental. Complementation with an editing‐deficient ADAR1 (Adar1P195A/E861A), or the loss of MDA5, rescues phenotypes in the Adar1P195A/− mice.