Danio rerio
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ABSTRACT:
PROVIDER: PRJNA185410 | ENA |
REPOSITORIES: ENA
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Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients 4 Control sibling samples (sample= 10 pooled larvae) and 4 Nav1.1 mutants (sample= 10 pooled larvae) were collected at 6 dpf (days post fertilization). The Nav1.1 mutants were selected based on phenotype (dark color).
2014-01-04 | E-GEOD-43312 | biostudies-arrayexpress
Project description:Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome (DS), is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development, and persistent drug-resistant seizures. One of its primary monogenic causes is a mutation in SCN1A (Nav1.1), a type I voltage-gated sodium channel. In mice, Nav1.1 mutation is associated with reduced sodium current, altered interneuron firing, cognitive deficits, autistic-like traits and seizures. Here we describe a larval zebrafish Nav1.1 mutant that recapitulates salient features of the human SCN1A mutation phenotype. Between three and seven days post-fertilization, Nav1.1 mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Transcriptomic analysis of Nav1.1 mutants was remarkable for the relatively small fraction of genes that were differentially expressed (~2%) and the lack of compensatory changes in expression for other SCN subunits. Pharmacological studies confirmed an antiepileptic action for the ketogenic diet, benzodiazepine, valproate, potassium bromide and stiripentol in Nav1.1 mutants; acetazolamide, phenytoin, ethosuximide had no effect, carbamazepine and vigabatrin made seizures worse. Using this mutant, we screened a chemical library of 320 compounds and identified four compounds that reduced spontaneous seizure-like behavior and one compound (clemizole) that inhibited convulsive behavior and electrographic seizures. Drug-resistant scn1a zebrafish mutants described here represent a new direction in modeling pediatric epilepsy and could be used to identify novel lead compounds for DS patients
2014-01-04 | GSE43312 | GEO
Project description:SCN1A, encoding the sodium channel protein type 1 alpha subunit, is the most implicated gene in epilepsy. Pathogenic loss-of-function variants that result in SCN1A haploinsufficiency cause the most common DEE, known as Dravet syndrome (DS). Pathogenic gain-of-function variants have been found to cause a more severe, early-onset epilepsy syndrome that is distinct from DS. Here, we investigated DNA methylation patterns in these individuals with SCN1A variants.
2024-10-25 | GSE280241 | GEO
Project description:Dravet syndrome is a severe, early-onset epileptic encephalopathy frequently resulting from de novo mutations of SCN1A. Mice with heterozygous deletion of Scn1a (Scn1a+/-) model many features of Dravet syndrome, including spontaneous seizures and premature lethality. Scn1a+/- mice exhibit variable phenotype penetrance and expressivity dependent upon the strain background. On the 129S6/SvEvTac (129) strain, Scn1a+/- mice do not display an overt phenotype. However Scn1a+/- mice on the [129S6xB6]F1 strain (F1.Scn1a+/-) exhibit juvenile-onset spontaneous seizures and premature lethality. QTL mapping identified several modifier loci responsible for strain-dependent differences in survival of Scn1a+/- mice, but these loci do not account for all the observed phenotypic variance. Global RNA-seq analysis was performed to identify additional genes and pathways that may contribute to variable phenotypes. Hippocampal gene expression was analyzed in wild-type (WT) and Scn1a+/- mice on both F1 and 129 strains, at two time points during disease development. There were few gene expression differences between 129.WT and 129. Scn1a+/- mice and approximately 100 genes with small expression differences (6-36%) between F1.WT and F1.Scn1a+/- mice. Strain-specific gene expression differences were more pronounced, with dozens of genes with >1.5-fold expression differences between 129 and F1 strains. Age-specific and seizure-related gene expression differences were most prominent, with hundreds of genes with >2-fold differences in expression were identified between groups with and without seizures, suggesting potential differences in developmental trajectory and/or homeostatic plasticity during disease onset. Global expression differences in the context of Scn1a deletion may account for strain-dependent variation in seizure susceptibility and survival observed in Scn1a+/- mice.
2018-10-26 | GSE112627 | GEO
Project description:Dravet syndrome (DS) is a severe epileptic encephalopathy caused by heterozygous loss-of-function mutations in the SCN1A gene, indicating a haploinsufficient genetic mechanism underlining this pathology. Here, we tested whether dCas9-mediated Scn1a gene activation could rescue Scn1a haploinsufficiency and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screeened sgRNAs for their ability to stimulate Scn1a gene transcription in association with the dCas9 activation system. Interestingly, we identified one single sgRNA able to significantly increase Scn1a gene expression levels in cell lines as well as in primary neurons, with high specificity. Accordingly, levels of Nav1.1 protein were sufficiently augmented to potentiate firing ability of wild-type immature GABAergic interneurons. A similar effect in activating the Scn1a transcription was elicited in Dravet GABAergic interneurons rescuing their dysfunctional properties. To determine whether this approach could have therapeutic effect, we packaged adeno-associated viruses with the Scn1a-dCas9 activation system and showed their ability to ameliorate the febrile epileptic crises in DS mice. Our results pave the way for exploiting the dCas9-based gene activation as an effective and targeted approach to DS and other similar disorders resulting from altered gene dosage.
2019-03-05 | GSE111436 | GEO
Project description:Discovering miRNA regulatory networks in Holt-Oram Syndrome using a Zebrafish model [array]
| PRJNA271001 | ENA
Project description:The exon junction complex (EJC) is composed of three core proteins Rbm8a, Magoh and Eif4a3 and is thought to play a role in several post-transcriptional processes. In this study we focus on understanding the role of EJC in zebrafish development. We identified transcriptome-wide binding sites of EJC in zebrafish via RNA:protein immunoprecipitation followed by deep sequencing (RIP-Seq). We find that, as in human cells, zebrafish EJC is deposited about 24 nts upstream of exon-exon junctions. We also identify transcripts regulated by Rbm8a and Magoh in zebrafish embryos using whole embryo RNA-seq from rbm8a mutant, magoh mutant and wild-type sibling embryos. This study shows that nonsense mediated mRNA decay is dysregulated in zebrafish EJC mutants.
2019-07-30 | GSE135019 | GEO
Project description:In this study we recapitulated in the mouse, an SCN1A mutation found in a human Dravet syndrome (DS) patient. The targeted mutation, NC_000068.7:g.66293870C>G (GRCm38.p6) lies in a highly conserved alternate poison exon (20N) of the mouse Scn1a. We performed molecular and behavioral analysis of Scn1a +/- mice and Scn1a +/+ littermate controls. We found that the mutation causes Scn1a mRNA and protein levels to be reduced by about 50% in brain compared to control mice. In addition, the Scn1a +/- mice exhibit behavioral phenotypes seen in previous DS model mice models. We performed qPCR and RNA-seq analysis of the brains of four Scn1a +/- mice and four Scn1a +/+ littermate controls. There was a ~50% reduction in Scn1a RNA-seq counts in Scn1a +/- mice. Our data provides evidence that the mutation causes increased inclusion of the poison exon 20N in Scn1a transcripts leading to nonsense mediated decay and reduction in protein levels.
2020-08-01 | GSE153461 | GEO
Project description:Discovering miRNA regulatory networks in Holt-Oram Syndrome using a Zebrafish model [miRNA-seq]
| PRJNA271079 | ENA