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• W2999444844 abstract "Neurodevelopmental disorder with involuntary movements (Online Mendelian Inheritance in Man: 617493) is a severe, early onset neurologic condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the <i>GNAO1</i> gene cause neurodevelopmental disorder with involuntary movements. G<i>α</i>_o, the gene product of <i>GNAO1</i>, is the alpha subunit of G_o, a member of the heterotrimeric G_i/o family of G proteins. G_o is found abundantly throughout the brain, but the pathophysiological mechanisms linking G<i>α</i>_o functions to clinical manifestations of <i>GNAO1-</i>related disorders are still poorly understood. One of the most common mutant alleles among the <i>GNAO1</i> encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in <i>Gnao1</i>^{<i>+/</i>R209H} mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the neurodevelopmental disorder with involuntary movements 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 <i>Gnao1</i>, the <i>Gnao1</i>^{<i>+/R209H</i>} mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from wild-type (WT) mice, but the nucleotide exchange rate of mutant R209H G<i>α</i>_o was 6.2× 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 <i>Gnao1</i>^{<i>+/R209H</i>} mice mirror elements of the patient phenotype and respond to an approved pharmacological agent. <h3>SIGNIFICANCE STATEMENT</h3> Children with de novo mutations in the <i>GNAO1</i> gene may present with movement disorders with limited effective therapeutic options. The most common mutant variant seen in children with <i>GNAO1</i>-associated movement disorder is R209H. Here we show, using a novel <i>Gnao1</i>^{<i>+/R209H</i>} mouse, that there is a clear behavioral phenotype that is suppressed by risperidone. However, risperidone also affects wild-type mouse activity, so its effects are not selective for the <i>GNAO1</i>-associated movement disorder." @default.
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• W2999444844 date "2020-01-06" @default.
• W2999444844 modified "2023-09-28" @default.
• W2999444844 title "Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone" @default.
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• W2999444844 doi "https://doi.org/10.1124/jpet.119.262733" @default.
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