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

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 gene cause neurodevelopmental disorder with involuntary movements. G the gene product of , is the alpha subunit of G, a member of the heterotrimeric G family of G proteins. G is found abundantly throughout the brain, but the pathophysiological mechanisms linking G functions to clinical manifestations of related disorders are still poorly understood. One of the most common mutant alleles among the encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in 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 , the 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 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 mice mirror elements of the patient phenotype and respond to an approved pharmacological agent. SIGNIFICANCE STATEMENT: Children with de novo mutations in the gene may present with movement disorders with limited effective therapeutic options. The most common mutant variant seen in children with -associated movement disorder is R209H. Here we show, using a novel 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 -associated movement disorder.