RT Journal Article SR Electronic T1 Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone JF bioRxiv FD Cold Spring Harbor Laboratory SP 662031 DO 10.1101/662031 A1 Casandra L. Larrivee A1 Huijie Feng A1 Jeffrey R. Leipprandt A1 Elena Y. Demireva A1 Huirong Xie A1 Richard R. Neubig YR 2019 UL http://biorxiv.org/content/early/2019/06/06/662031.abstract AB Neurodevelopmental delay 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. 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.HighlightsGnao1 +/R209H mice display hyperlocomotion and gait abnormalities.Gnao1 +/R209H mice do not show enhanced seizure susceptibility as was observed in two other Gnao1 mutant mouse modelsSimilar to patients with GNAO1+/R209H mutations, the Gnao1+/R209H mutant mice show only a movement phenotype and no epilepsyHyperlocomotion of Gnao1 +/R209H mice was alleviated by risperidoneACAdenylyl CyclasecAMPCyclic adenosine monophosphateEIEE17Early infantile epileptic encephalopathy 17GOFGain-of-functionGPCRG-protein coupled receptorLOFLoss-of-functionNEDIMNeurodevelopment disorder with involuntary movementsRNPRibonucleoproteintracrRNATrans-activating crRNAcrRNACRISPR RNAssODNSingle-stranded oligodeoxynucleotideDSBDouble strand DNA breakPAMProtospacer-adjacent motif