ArticleAmerican journal of human genetics2013
De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers, 2 of them syntheses that pooled it.
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Who cites it
120 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review.International journal of molecular sciences · 2021Pooled it
- A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood.Molecular autism · 2019Pooled it
- GNAI2 activating variants and MAGIS syndrome: long-term endocrine and growth outcome.Hormones (Athens, Greece) · 2026Review
- Precision Medicine in Epilepsy: Diagnostic Yield by Next-Generation Sequencing and Genotype-Phenotype Findings in a Romanian Cohort.International journal of molecular sciences · 2026Article
- Consensus-based follow-up and treatment registry for GNAO1-associated disorder.Developmental medicine and child neurology · 2026Article
- Gene supplementation therapy restores motor deficits in Gnao1[C215Y] mice and proves broad efficacy in C. elegans model.Acta neuropathologica communications · 2026Article
- Longitudinal Phenotypic Trajectories in GNAO1-Related Disorders: Defining Disease Progression and Clinical Profiles.Annals of neurology · 2026Article
- A Novel GNAO1 Variant Associated With Variable and Mild Phenotypes in a Spanish Family.Journal of movement disorders · 2026Article
- 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
- Small-molecule inhibitor of Gαo for GNAO1 encephalopathy.Bioscience reports · 2026Article
- Dissecting GPCR Contributions to Gαo-Dependent Motor Dysfunction inBiomedicines · 2026Article
- Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Case Report: Early infantile drug-resistant epilepsy and gastrointestinal dysmotility associated with aFrontiers in pediatrics · 2026Article
- Deciphering a mechanistic basis for the pathological effect of the GNAO1 E246K variant in neurodevelopmental disorder.BBA advances · 2026Article
- Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights.Molecular autism · 2025Article
- Article
- Exploring the Impact of Dyskinetic Crises in GNAO1-Related Disorders: A Survey for Parents and Caregivers.Movement disorders clinical practice · 2025Article
- Neuronal oscillatory imbalances in GNAO1-related disorders associated with disease severity.Epilepsia · 2025Observational
60 more citing papers are in PubMed but not listed here.
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Abstract
Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.
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