ArticleMammalian genome : official journal of the International Mammalian Genome Society2014
Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?
Article in Mammalian genome : official journal of the International Mammalian Genome Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 40 citations in OpenAlex.
- 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
- Identification of three novel GNAO1 variants in a Chinese cohort with GNAO1 encephalopathy: expanding the clinical and genetic spectrum.Orphanet journal of rare diseases · 2025Article
- Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.Molecular therapy. Nucleic acids · 2025Article
- CB1R activates the epilepsy-associated protein Go to regulate neurotransmitter release and synaptic plasticity in the cerebellum.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Strain-dependent effects on neurobehavioral and seizure phenotypes inbioRxiv : the preprint server for biology · 2023Article
- CRISPR/Cas9-generated mouse model with humanizing single-base substitution in theFrontiers in genome editing · 2023Article
- Phenotypic Diversity in GNAO1 Patients: A Comprehensive Overview of Variants and Phenotypes.Human mutation · 2023Review
- Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.Human molecular genetics · 2022Article
- Mouse models characterize GNAO1 encephalopathy as a neurodevelopmental disorder leading to motor anomalies: from a severe G203R to a milder C215Y mutation.Acta neuropathologica communications · 2022Article
- Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 ofCells · 2021Article
- Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.Epilepsia · 2019Article
- Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Review
- Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes.PloS one · 2019Article
- Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms.Journal of inherited metabolic disease · 2018Review
- Movement disorder inNeurology · 2017Article
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- GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females.Orphanet journal of rare diseases · 2016Article
- Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.European journal of human genetics : EJHG · 2016Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
G protein-coupled receptors strongly modulate neuronal excitability but there has been little evidence for G protein mechanisms in genetic epilepsies. Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known. The GNAO1 gene product, Gαo, negatively regulates neurotransmitter release. Here, we report a dominant murine model of Gnao1-related seizures and sudden death. We introduced a genomic gain-of-function knock-in mutation (Gnao1 (+/G184S)) that prevents Go turnoff by Regulators of G protein signaling proteins. This results in rare seizures, strain-dependent death between 15 and 40 weeks of age, and a markedly increased frequency of interictal epileptiform discharges. Mutants on a C57BL/6J background also have faster sensitization to pentylenetetrazol (PTZ) kindling. Both premature lethality and PTZ kindling effects are suppressed in the 129SvJ mouse strain. We have mapped a 129S-derived modifier locus on Chromosome 17 (within the region 41-70 MB) as a Modifer of G protein Seizures (Mogs1). Our mouse model suggests a novel gain-of-function mechanism for the newly defined subset of epileptic encephalopathy (EIEE17). Furthermore, it reveals a new epilepsy susceptibility modifier Mogs1 with implications for the complex genetics of human epilepsy as well as sudden death in epilepsy.
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