Research Article: Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Huijie Feng, Casandra L. Larrivee, Elena Y. Demireva, Huirong Xie, Jeff R. Leipprandt, Richard R. Neubig, Yuqing Li.


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.

Here we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model.

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), which has not been found in patients, was also studied for comparison.

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.

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.

Partial Text

Neurodevelopmental Disorder with Involuntary Movements (NEDIM) is a newly defined neurological disorder associated with mutations in GNAO1. It is characterized by “hypotonia, delayed psychomotor development, and infantile or childhood onset of hyperkinetic involuntary movements” (OMIM 617493). NEDIM is monogenetic and associated with GOF mutations in GNAO1 [1]. The GNAO1 gene has also been associated with early infantile epileptic encephalopathy 17 (EIEE17; OMIM 615473). However, 36% of patients showed both epilepsy and movement disorder phenotypes (G40R, G45R, S47G, I56T, T191_F197del, L199P, G203R, R209C, A227V, Y231C and E246G) [2].

In this report, we describe the first mouse model carrying a human GNAO1 mutation associated with disease and we provide evidence to support the concept that GOF mutations are associated with movement disorder [1]. Heterozygous mice carrying the G203R mutation in Gnao1 exhibit both a mild increase in seizure propensity and evidence of abnormal movements. This fits precisely with the variable seizure pattern of the children who carry this mutation as well as their severe choreoathetotic movements [2, 15–17, 19, 51, 53]. Also, we examined a possible movement phenotype in mice carrying the RGS-insensitive GOF mutant (Gnao1+/G184S) that we reported previously to have a mild seizure phenotype [14]. This mutation has not been reported in humans to our knowledge. As predicted from our mechanistic model [1, 2], the Gnao1 G184S mutant mice also show movement abnormalities.




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