ArticleActa neuropathologica communications2022
Mouse models characterize GNAO1 encephalopathy as a neurodevelopmental disorder leading to motor anomalies: from a severe G203R to a milder C215Y mutation.
Article in Acta neuropathologica communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 36 citations in OpenAlex.
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- G-protein regulatory network governs receptor internalization dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Conditional Modeling of GNAO1 Disorder Dissociates Circuit Specific Contributions to Pathology and Rationalizes Ameliorative Strategies.Movement disorders : official journal of the Movement Disorder Society · 2026Article
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- Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights.Molecular autism · 2025Article
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- Dominant Gα mutations in human disease: unifying mechanisms and treatment strategies.EMBO molecular medicine · 2025Review
- Novel Mutation at Cys225 inMedComm · 2025Article
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- Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.Molecular therapy. Nucleic acids · 2025Article
- Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.Biomolecules · 2025Review
- Decoding GNAO1 mutations usingFrontiers in cellular neuroscience · 2025Review
- Diverse faces of GNAO1: mild forms in epilepsy and autism.Journal of neurology · 2024Article
- GPCR-G protein selectivity revealed by structural pharmacology.The FEBS journal · 2024Review
- Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies.The Journal of clinical investigation · 2024Article
- Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant.Molecular diagnosis & therapy · 2024Article
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- Molecular annotation of G protein variants in a neurological disorder.Cell reports · 2023Article
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- PediatricNeural regeneration research · 2023Article
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GNAO1 encephalopathy characterized by a wide spectrum of neurological deficiencies in pediatric patients originates from de novo heterozygous mutations in the gene encoding Gαo, the major neuronal G protein. Efficient treatments and even the proper understanding of the underlying etiology are currently lacking for this dominant disease. Adequate animal models of GNAO1 encephalopathy are urgently needed. Here we describe establishment and characterization of mouse models of the disease based on two point mutations in GNAO1 with different clinical manifestations. One of them is G203R leading to the early-onset epileptic seizures, motor dysfunction, developmental delay and intellectual disability. The other is C215Y producing much milder clinical outcomes, mostly-late-onset hyperkinetic movement disorder. The resultant mouse models show distinct phenotypes: severe neonatal lethality in GNAO1[G203R]/ + mice vs. normal vitality in GNAO1[C215Y]/ + . The latter model further revealed strong hyperactivity and hyperlocomotion in a panel of behavioral assays, without signs of epilepsy, recapitulating the patients' manifestations. Importantly, despite these differences the two models similarly revealed prenatal brain developmental anomalies, such as enlarged lateral ventricles and decreased numbers of neuronal precursor cells in the cortex. Thus, our work unveils GNAO1 encephalopathy as to a large extent neurodevelopmental malady. We expect that this understanding and the tools we established will be instrumental for future therapeutic developments.
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