Investigating DNA methylation in individuals with pathogenic variants in SCN1A
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ABSTRACT:
PROVIDER: PRJNA1177435 | ENA |
REPOSITORIES: ENA
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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: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:Pathogenic Structural Variants in Leukemia Genomes
| PRJEB50975 | ENA
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: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:Changes in the amino acid sequences of proteins cause thousands of human genetic diseases. However, only a subset of variants in any protein is typically pathogenic, with variants having a diversity of molecular consequences. Determining which of the thousands of possible variants in any protein have similar molecular effects is very challenging, but crucial for identifying pathogenic variants, determining disease mechanisms, understanding clinical phenotypic variation, and developing targeted therapeutics. Here we present a general method to classify variants by their molecular effects that we term intramolecular genetic interaction profiling. The approach relies on the principle that variants with similar molecular consequences have similar genetic interactions with other variants in the same protein. These intramolecular genetic interactions are straightforward to quantify for any protein with a selectable function. We apply intramolecular genetic interaction profiling to amyloid beta, the protein that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). Genetic interactions identify two classes of gain-of-function variants, with all known familial Alzheimer’s disease variants having very similar genetic interaction profiles, consistent with a common gain-of-function mechanism leading to pathology. We believe that intramolecular genetic interaction profiling is a powerful approach for classifying variants in disease genes that will empower rare variant association studies and the discovery of disease mechanisms.
2023-11-15 | GSE247583 | GEO
Project description:Background: Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. Methods: To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We bred a transgenic mouse line with deletion of the extended evolutionarily-conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alteration in behavior. Results: Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and some behavioral deficits. Conclusions: This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence
2021-03-26 | GSE169481 | GEO
Project description:We identified pathogenic and likely pathogenic variants in 17.8% of the patients within a wide range of cancer types. In particular, mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. In total, 22 BRCA1 and BRCA2 germline variant were identified in 12 different cancer types, of which 10 (45%) variants were not previously identified in these patients. Pathogenic germline variants were predominantly found in DNA repair pathways; approximately half of the variants were within genes involved in homologous recombination repair. Loss of heterozygosity and somatic second hits were identified in several of these genes, supporting possible causality for cancer development. A potential treatment target based on pathogenic germline variant could be suggested in 25 patients (4%).
2019-05-11 | GSE131027 | GEO
Project description:Background: Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. Methods: To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We bred a transgenic mouse line with deletion of the extended evolutionarily-conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alteration in behavior. Results: Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and some behavioral deficits. Conclusions: This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence
2021-03-26 | GSE169485 | GEO
Project description:Patients suspected of adenomatous polyposis were included. The criteria used were more than 10 polyps observed under colonoscopy, and pathological confirmation of adenoma. Clinical data and pedigree information were collected. The variants of 139 genes associated with different hereditary cancers and polyposis were screened by NGS, which was performed by Genetron Health on the HiSeqX-ten sequencing platform.
| 2383243 | ecrin-mdr-crc