Aicardi-Goutières syndrome is a severe progressive genetic disorder in young children presenting with symptoms such as encephalopathy, developmental delays, loss of intellectual abilities, and motor control impairments. Symptoms of AGS typically present themselves within the first year of life, with early-onset beginning at birth and later-onset developing within the first few weeks to months of life. AGS has been linked to mutations in seven different protein-coding genes that are involved in DNA/RNA metabolism and sensing. However, the molecular mechanism by which these mutations impact the neuropathogenesis of AGS remains unclear. As a result, there are no effective treatment measures to stop the progression of AGS.

To study the mechanism behind these mutations, we created a mouse model by introducing a mutation at the ADAR1 coding gene, one of the identified protein-coding genes, through the use of CRISPR/Cas-9 technology into the mouse genome. Through breeding, a double gene mutation, ADAR1 and MDA-5, mouse model was developed. RNA sequencing analysis was used to measure the levels of RNA editing in brain mRNA substrates of ADAR1. Additionally, phenotype, gene expression, innate immune pathway activation, and pathologic studies (such as RNA in situ hybridization and immunohistochemistry) were used to identify potential disease mechanisms in the mouse model. 

Through the mouse model, we established the underlying mechanism of the ADAR1 mutation in AGS. This mutated mouse model exhibited changes in RNA editing of neural transcripts, resulting in heightened IFN-stimulated gene expression. The in situ hybridization showed increased expression of ISG in specific cell-types. Mutant mice presented with early-onset astrocytosis and microgliosis and late-stage calcification in deep white matter. ISG activation and neuroglial reaction are blocked due to the removal of the cytosolic RNA receptor MDA-5. 

The ADAR-1 mutation results in early-onset encephalopathy leading to IFN pathway activation in mice, which is MDA5 dependent.