Heterozygous ADAR mutant mice exhibit RNA sensing-dependent neuroinflammation and phenotypes associated with Aicardi-Goutières syndrome

The ADAR^G1007R mutation is frequently found in type six Aicardi-Goutières syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients, and is distinct in having a phenotype in heterozygotes. To define the mechanisms underlying this disease, we developed an ADAR^G1007 heterozygous mouse model that recapitulates the genetic and inflammatory features of individuals with ADAR^G1007R AGS. These mice exhibited increased astrocytosis and microgliosis and interferon-stimulated gene (ISG) expression within deep brain areas. Additionally, brain inflammation was reversed by deletion of MDA5, which blocks cellular RNA sensing. Analysis of embryonic RNAs show the G1007R mutation also interrupts the splicing donor site in RNA transcripts, thereby altering ADAR1 RNA splicing and depleting the ADAR1 protein. Collectively, this study reports an animal model for AGS manifesting a heterozygous phenotype, reveals molecular defects associated with the ADAR^G1007R mutation, and demonstrates that MDA5-dependent RNA sensing contributes to neuroinflammation.