Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Abstract

Neurodevelopmental disorder with involuntary movements (NEDIM, OMIM: 617493) is a severe, early onset neurological condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause NEDIM. Gαo, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G-proteins. Go is found abundantly throughout the brain but the pathophysiological mechanisms linking Gαo functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1+/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the NEDIM clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1+/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from WT mice but the nucleotide exchange rate of mutant R209H Gαo was 9 times faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1+/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent.

Restoration of the GTPase activity and cellular interactions of Gα o mutants by Zn 2+ in GNAO1 encephalopathy models

“…To seek understanding of the molecular etiology of GNAO1 encephalopathy, we focused on the most frequent pathologic Gα o mutants and first probed their basic biochemical properties: GTP uptake and hydrolysis, in comparison to the wild-type protein. The GTP uptake analysis has so far been performed for three GNAO1 encephalopathy mutants: Q52P and Q52R displayed complete loss of the GTP uptake ( 14 ), while R209H was reported to display a faster GTP uptake ( 15 ). We applied the nonhydrolyzable fluorescent BODIPY-GTPγS (guanosine 5′-[γ-thio]triphosphate) ( 4 , 16 – 18 ) to monitor the GTP uptake properties of the wild-type protein and three Gα o mutant variants: G203R, R209C, and E246K.…”

Both subthalamic and pallidal deep brain stimulation are effective for GNAO1-associated dystonia: three case reports and a literature review

“…According to the documented literature, risperidone was effective for both a mouse model and patients with GNAO1 -related movement disorders. 14,25 However, tetrabenazine, a representative vesicular monoamine transporter-2 (VMAT-2) inhibitor, was the most successful medication for controlling chorea symptoms among patients with GNAO1 variants. 5,15,16 In addition, antiepileptics and other agents, such as levodopa, are the standard pharmacological treatments, but they show only partial effectiveness.…”

“…25 g three times per day). When he was admitted to the hospital at the age of 17, his movement symptoms had worsened,…”

Mice With Monoallelic GNAO1 Loss Exhibit Reduced Inhibitory Synaptic Input To Cerebellar Purkinje Cells

“…Mutations in Gao result in GNAO1 encephalopathies which include severe epilepsy (Nakamura et al, 2013) or movement disorders (Ananth et al, 2016;Feng, Khalil, Neubig, & Sidiropoulos, 2018;Saitsu et al, 2016) with profound impacts on affected children. While cellbased studies (Feng et al, 2018;Feng et al, 2017) and animal behavioral models (Feng et al, 2019;Larrivee et al, 2019) have provided some mechanistic information about the human GNAO1 mutations, there have been no neurophysiological studies of effects on synaptic transmission. Here, we show that a LOF mutant mouse with haploinsufficient Gao protein has impaired inhibitory signaling in cerebellar PCs, which is most likely due to increased levels of free Gbg in inhibitory neurons.…”