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Gabra2 is a genetic modifier of Dravet syndrome in mice
Pathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458207/ https://www.ncbi.nlm.nih.gov/pubmed/34086081 http://dx.doi.org/10.1007/s00335-021-09877-1 |
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author | Hawkins, Nicole A. Nomura, Toshihiro Duarte, Samantha Barse, Levi Williams, Robert W. Homanics, Gregg E. Mulligan, Megan K. Contractor, Anis Kearney, Jennifer A. |
author_facet | Hawkins, Nicole A. Nomura, Toshihiro Duarte, Samantha Barse, Levi Williams, Robert W. Homanics, Gregg E. Mulligan, Megan K. Contractor, Anis Kearney, Jennifer A. |
author_sort | Hawkins, Nicole A. |
collection | PubMed |
description | Pathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a(+/−)) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a(+/−) mice recapitulate features of Dravet syndrome, including spontaneous seizures, sudden death, and cognitive/behavioral deficits. Scn1a(+/−) mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no spontaneous seizures. In contrast, admixture with C57BL/6J (B6) results in epilepsy and premature lethality. We previously mapped Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABA(A) α2 subunit, was nominated as a candidate modifier at Dsm1. Direct measurement of GABA(A) receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this deletion reestablished normal levels of Gabra2 expression. In this study, we used B6 mice with a repaired Gabra2 allele to evaluate Gabra2 as a genetic modifier of severity in Scn1a(+/−) mice. Gabra2 repair restored transcript and protein expression, increased abundance of α2-containing GABA(A) receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a(+/−) mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome, and support enhancing function of α(2)-containing GABA(A) receptors as treatment strategy for Dravet syndrome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00335-021-09877-1. |
format | Online Article Text |
id | pubmed-8458207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-84582072021-10-07 Gabra2 is a genetic modifier of Dravet syndrome in mice Hawkins, Nicole A. Nomura, Toshihiro Duarte, Samantha Barse, Levi Williams, Robert W. Homanics, Gregg E. Mulligan, Megan K. Contractor, Anis Kearney, Jennifer A. Mamm Genome Article Pathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a(+/−)) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a(+/−) mice recapitulate features of Dravet syndrome, including spontaneous seizures, sudden death, and cognitive/behavioral deficits. Scn1a(+/−) mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no spontaneous seizures. In contrast, admixture with C57BL/6J (B6) results in epilepsy and premature lethality. We previously mapped Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABA(A) α2 subunit, was nominated as a candidate modifier at Dsm1. Direct measurement of GABA(A) receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this deletion reestablished normal levels of Gabra2 expression. In this study, we used B6 mice with a repaired Gabra2 allele to evaluate Gabra2 as a genetic modifier of severity in Scn1a(+/−) mice. Gabra2 repair restored transcript and protein expression, increased abundance of α2-containing GABA(A) receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a(+/−) mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome, and support enhancing function of α(2)-containing GABA(A) receptors as treatment strategy for Dravet syndrome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00335-021-09877-1. Springer US 2021-06-04 2021 /pmc/articles/PMC8458207/ /pubmed/34086081 http://dx.doi.org/10.1007/s00335-021-09877-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hawkins, Nicole A. Nomura, Toshihiro Duarte, Samantha Barse, Levi Williams, Robert W. Homanics, Gregg E. Mulligan, Megan K. Contractor, Anis Kearney, Jennifer A. Gabra2 is a genetic modifier of Dravet syndrome in mice |
title | Gabra2 is a genetic modifier of Dravet syndrome in mice |
title_full | Gabra2 is a genetic modifier of Dravet syndrome in mice |
title_fullStr | Gabra2 is a genetic modifier of Dravet syndrome in mice |
title_full_unstemmed | Gabra2 is a genetic modifier of Dravet syndrome in mice |
title_short | Gabra2 is a genetic modifier of Dravet syndrome in mice |
title_sort | gabra2 is a genetic modifier of dravet syndrome in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458207/ https://www.ncbi.nlm.nih.gov/pubmed/34086081 http://dx.doi.org/10.1007/s00335-021-09877-1 |
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