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| Status |
Public on Jul 28, 2022 |
| Title |
Expression data from the hippocampus of epileptic mice carrying two different pathogenic de novo mutations in the hyperpolarization-activated, cyclic nucleotide-gated, non-selective cation channel gene Hcn1 in comparison to wildtype controls |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Expression data from the hippocampus of epileptic mice carrying two different pathogenic de novo mutations in the hyperpolarization-activated, cyclic nucleotide-gated, non-selective cation channel gene Hcn1 (p.G391D in human corresponding to G380D in mouse; p.M153I in human corresponding to M142I in mice) in comparison to wildtype controls.
De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo mutations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the need to tailor effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.
This dataset contains a comparison of the gene expression profile of the hippocampus of epileptic mice carrying either the pathogenic G380D (GD) variant (Hcn1GD/+ mice), or the M142I (MI) variant (Hcn1MI/+ mice) in Hcn1 in comparison to wildtype (WT) controls (Hcn1+/+ mice).
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| Overall design |
Four WT controls, four heterozygous mutant Hcn1GD/+ males, and four heterozygous mutant Hcn1MI/+ male mice of the same age were selected for RNA extraction from both hippocampi and hybridization on Clariom™ S Mouse arrays.
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| Contributor(s) |
Santoro B, Isbrandt D, Stockebrand M, Merseburg A |
| Citation(s) |
35972069 |
| Submission date |
Jul 24, 2022 |
| Last update date |
Sep 27, 2022 |
| Contact name |
Andrea Merseburg |
| E-mail(s) |
andrea.merseburg@enp.org
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| Organization name |
German Center for Neurodegenerative Diseases (DZNE), Bonn, and University of Cologne, Cologne, Germany
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| Department |
Institute for Molecular and Behavioral Neuroscience
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| Lab |
Experimental Neurophysiology
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| Street address |
Kerpener Str. 62
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| City |
Cologne |
| State/province |
North Rhine-Westphalia |
| ZIP/Postal code |
50937 |
| Country |
Germany |
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| Platforms (1) |
| GPL23038 |
[Clariom_S_Mouse] Affymetrix Clariom S Assay, Mouse (Includes Pico Assay) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA861865 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE209630_RAW.tar |
17.1 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data provided as supplementary file |
| Processed data included within Sample table |
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