ArticleHuman molecular genetics2022
Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 42 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
- Developing a New Approach Methodology Framework to Assess Biological Responses to Nanoplastics: Insights from Polystyrene and Biodegradable Particles.Nanomaterials (Basel, Switzerland) · 2026Article
- Dissecting GPCR Contributions to Gαo-Dependent Motor Dysfunction inBiomedicines · 2026Article
- C. elegans: An elegant experimental system for the study of cilia biology.Seminars in cell & developmental biology · 2025Review
- Dominant Gα mutations in human disease: unifying mechanisms and treatment strategies.EMBO molecular medicine · 2025Review
- Positive Effects of Caffeine Therapy in a Girl with PDE2A-Related Paroxysmal Dyskinesia.Movement disorders clinical practice · 2025Article
- Decoding GNAO1 mutations usingFrontiers in cellular neuroscience · 2025Review
- Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies.The Journal of clinical investigation · 2024Article
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- High-throughput light sheet imaging of adult and larvalRSC advances · 2024Article
- A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.Traffic (Copenhagen, Denmark) · 2024Article
- See Elegans: Simple-to-use, accurate, and automatic 3D detection of neural activity from densely packed neurons.PloS one · 2024Article
- Matching variants for functional characterization of genetic variants.G3 (Bethesda, Md.) · 2023Article
- Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function.Annals of neurology · 2023Observational
- Article
- Back to the future through the wormhole: Caenorhabditis elegans as a preclinical model.Disease models & mechanisms · 2023Article
- Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.Molecular aspects of medicine · 2023Review
- Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.Brain : a journal of neurology · 2023Article
- Phenotypic Assessment of Pathogenic Variants inGenes · 2023Article
- Gln52 mutations inEpilepsy & behavior reports · 2023Article
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.
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