"Due to the increased availability of genetic screening, patients with idiopathic epilepsy and movement disorders are being identified with mutations in the GNAO1 gene. The GNAO1 gene encodes a heterotrimeric G protein subunit, Galphao, abundantly found within the brain. Patients with de novo mutations in GNAO1 specifically may have early onset seizure disorders and/or involuntary movements. These two phenotypes were later classified as early infantile epileptic encephalopathy (EIEE17) and... Show more"Due to the increased availability of genetic screening, patients with idiopathic epilepsy and movement disorders are being identified with mutations in the GNAO1 gene. The GNAO1 gene encodes a heterotrimeric G protein subunit, Galphao, abundantly found within the brain. Patients with de novo mutations in GNAO1 specifically may have early onset seizure disorders and/or involuntary movements. These two phenotypes were later classified as early infantile epileptic encephalopathy (EIEE17) and neurodevelopmental delay with involuntary movements (NEDIM) respectively. Previous work in our lab uncovered a pattern between the in vitro function of mutations and the type of disorder observed in patients. Loss-of-function mutations associated with EIEE17 while gain-of-function mutations or proteins with essentially normal function were seen in NEDIM. To determine whether this pattern could be replicated in vivo, heterozygous mutant mice were created using CRISPR/Cas9. Here we report the first mouse models of GNAO1 disorders, Gnao1+/G203R and Gnao1+/R209H. Using a variety of behavioral battery tests including open field, rotarod and digigait, we were able to show distinct behavioral patterns between the mutant mice. Using these models we began to explore preclinical drug repurposing and neural mechanisms."--Page ii. Show less
