Mouse Models of GNAO1 Associated Movement Disorder: Allele and sex specific differences in phenotypes
Background Infants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss of function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17) Gain of function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM) There is no animal model with a human mutant GNAO1 allele. Objectives Here we develop a mouse model carrying a human GNAO1 mutation and determine whether clinical features of the GNAO1 mutation including movement disorder would be evident in the mouse model. Methods A mouse Gnao1 knock in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock in (Gnao1+/G184S) was also studied for comparison. Results Gnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock in also showed movement related behavioral phenotypes but females were more strongly affected than males. Conclusions Gnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1 related movement disorders.