ArticleEpilepsia2020
Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans.
Article in Epilepsia, 2020. 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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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- Diverse species of animal models in epilepsy research: Progress and perspectives.Zoological research · 2025Review
- STXBP1 Syndrome: Biotechnological Advances, Challenges, and Perspectives in Gene Therapy, Experimental Models, and Translational Research.Biotech (Basel (Switzerland)) · 2025Review
- Characterisation and automated quantification of induced seizure-related behaviours in Xenopus laevis tadpoles.Journal of neurochemistry · 2024Article
- A De Novo Splicing Mutation ofInternational journal of molecular sciences · 2024Article
- Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans.PLoS genetics · 2024Article
- Functional analysis of epilepsy-associated GABAEpilepsia open · 2024Article
- Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition.bioRxiv : the preprint server for biology · 2024Article
- Article
- Functional analysis of epilepsy-linked pathogenic variants of the Munc18-1 gene in the inhibitory nervous system ofmicroPublication biology · 2024Article
- Matching variants for functional characterization of genetic variants.G3 (Bethesda, Md.) · 2023Article
- A Caenorhabditis elegans model of autosomal dominant adult-onset neuronal ceroid lipofuscinosis identifies ethosuximide as a potential therapeutic.Human molecular genetics · 2023Article
- Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.Brain : a journal of neurology · 2023Article
- Clinical variants inGenetics in medicine open · 2023Article
- Clemizole and trazodone are effective antiseizure treatments in a zebrafish model of STXBP1 disorder.Epilepsia open · 2022Article
- Clinical whole exome sequencing revealedSaudi journal of biological sciences · 2022Article
- Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans.Human molecular genetics · 2022Article
- Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction.Human molecular genetics · 2022Article
- Zebrafish Is a Powerful Tool for Precision Medicine Approaches to Neurological Disorders.Frontiers in molecular neuroscience · 2022Review
- Comparison of electrophysiological and motility assays to study anthelmintic effects in Caenorhabditis elegans.International journal for parasitology. Drugs and drug resistance · 2021Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
objectiveGenetic variants in STXBP1, which encodes the conserved exocytosis protein Munc18-1, are associated with a variety of infantile epilepsy syndromes. We aimed to develop an in vivo Caenorhabditis elegans model that could be used to test the pathogenicity of such variants in a cost-effective manner.
methodsThe CRISPR/Cas9 method was used to introduce a null mutation into the unc-18 gene (the C. elegans orthologue of STXBP1), thereby creating a paralyzed worm strain. We subsequently rescued this strain with transgenes encoding the human STXBP1/Munc18-1 protein (wild-type and eight different epilepsy-associated missense variants). The resulting humanized worm strains were then analyzed via behavioral, electrophysiological, and biochemical approaches.
resultsTransgenic expression of wild-type human STXBP1 protein fully rescued locomotion in both solid and liquid media to the same level as the standard wild-type worm strain, Bristol N2. Six variant strains (E59K, V84D, C180Y, R292H, L341P, R551C) exhibited impaired locomotion, whereas two (P335L, R406H) were no different from worms expressing wild-type STXBP1. Electrophysiological recordings revealed that all eight variant strains displayed less frequent and more irregular pharyngeal pumping in comparison to wild-type STXBP1-expressing strains. Four strains (V84D, C180Y, R292H, P335L) exhibited pentylenetetrazol-induced convulsions in an acute assay of seizure-like activity, in contrast to worms expressing wild-type STXBP1. No differences were seen between wild-type and variant STXBP1 strains in terms of mRNA abundance. However, STXBP1 protein levels were reduced to 20%-30% of wild-type in all variants, suggesting that the mutations result in STXBP1 protein instability. SIGNIFICANCE: The approach described here is a cost-effective in vivo method for establishing the pathogenicity of genetic variants in STXBP1 and potentially other conserved neuronal proteins. Furthermore, the humanized strains we created could potentially be used in the future for high-throughput drug screens to identify novel therapeutics.
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