Academic Journal
View in EDS
Linked Full Text

Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy

Bibliographic Details
Title: Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy
Authors: Wenxi Yu, Megan K. Mulligan, Robert W. Williams, Miriam H. Meisler
Source: HGG Advances, Vol 3, Iss 1, Pp 100064- (2022)
Publisher Information: Elsevier, 2022.
Publication Year: 2022
Collection: LCC:Genetics
Subject Terms: Scn8a, Gabra2, epilepsy, epileptic encephalopathy, genetic modifier, voltage-gated sodium channel, Genetics, QH426-470
More Details: Summary: De novo gain-of-function mutations of SCN8A are a significant cause of developmental and epileptic encephalopathy (DEE) (MIM: 614558). The severely affected individuals exhibit refractory seizures, developmental delay, and cognitive disabilities, often accompanied by impaired movement. Individuals with the identical SCN8A variant often differ in clinical course, suggesting a role for modifier genes in disease severity. In a previous study we demonstrated genetic linkage between a hypomorphic mutation in the Gabra2 gene and seizure severity in a mouse model of the human SCN8A pathogenic variant p.Arg1872Trp. Homozygosity for the hypomorphic Gabra2 mutation was associated with early seizure onset and shortened lifespan. We have now confirmed Gabra2 as the modifier gene using a knock-in allele that corrects the splice site variant in strain C57BL/6J. Correction of the Gabra2 variant restores transcript abundance, increases the age of seizure onset, and extends survival of the Scn8a mutant mice. GABRA2 encodes the α2 subunit of the GABAA receptor that provides inhibitory input to dendrites and the the axon initial segment of excitatory neurons. Quantitative variation in human GABAA receptor expression could contribute to variation in the severity of genetic epilepsies and suggests a potential therapeutic intervention.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2666-2477
Relation: http://www.sciencedirect.com/science/article/pii/S2666247721000452; https://doaj.org/toc/2666-2477
DOI: 10.1016/j.xhgg.2021.100064
Access URL: https://doaj.org/article/8a7008e3fe9542ceb4f3e110f42a7bd9
Accession Number: edsdoj.8a7008e3fe9542ceb4f3e110f42a7bd9
Database: Directory of Open Access Journals
FullText Links:
  – Type: other
    Url: https://resolver.ebsco.com:443/public/rma-ftfapi/ejs/direct?AccessToken=463EB4DA6B607C7DEA4A&Show=Object
Text:
  Availability: 0
CustomLinks:
  – Url: https://www.doi.org/10.1016/j.xhgg.2021.100064?
    Name: ScienceDirect (all content)-s8985755
    Category: fullText
    Text: View record from ScienceDirect
    MouseOverText: View record from ScienceDirect
  – Url: https://resolver.ebsco.com/c/xy5jbn/result?sid=EBSCO:edsdoj&genre=article&issn=26662477&ISBN=&volume=3&issue=1&date=20220101&spage=&pages=&title=HGG Advances&atitle=Correction%20of%20the%20hypomorphic%20Gabra2%20splice%20site%20variant%20in%20mouse%20strain%20C57BL%2F6J%20modifies%20the%20severity%20of%20Scn8a%20encephalopathy&aulast=Wenxi%20Yu&id=DOI:10.1016/j.xhgg.2021.100064
    Name: Full Text Finder (for New FTF UI) (s8985755)
    Category: fullText
    Text: Find It @ SCU Libraries
    MouseOverText: Find It @ SCU Libraries
  – Url: https://doaj.org/article/8a7008e3fe9542ceb4f3e110f42a7bd9
    Name: EDS - DOAJ (s8985755)
    Category: fullText
    Text: View record from DOAJ
    MouseOverText: View record from DOAJ
Header DbId: edsdoj
DbLabel: Directory of Open Access Journals
An: edsdoj.8a7008e3fe9542ceb4f3e110f42a7bd9
RelevancyScore: 938
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 937.599182128906
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Wenxi+Yu%22">Wenxi Yu</searchLink><br /><searchLink fieldCode="AR" term="%22Megan+K%2E+Mulligan%22">Megan K. Mulligan</searchLink><br /><searchLink fieldCode="AR" term="%22Robert+W%2E+Williams%22">Robert W. Williams</searchLink><br /><searchLink fieldCode="AR" term="%22Miriam+H%2E+Meisler%22">Miriam H. Meisler</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: HGG Advances, Vol 3, Iss 1, Pp 100064- (2022)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: Elsevier, 2022.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2022
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: LCC:Genetics
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Scn8a%22">Scn8a</searchLink><br /><searchLink fieldCode="DE" term="%22Gabra2%22">Gabra2</searchLink><br /><searchLink fieldCode="DE" term="%22epilepsy%22">epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22epileptic+encephalopathy%22">epileptic encephalopathy</searchLink><br /><searchLink fieldCode="DE" term="%22genetic+modifier%22">genetic modifier</searchLink><br /><searchLink fieldCode="DE" term="%22voltage-gated+sodium+channel%22">voltage-gated sodium channel</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink><br /><searchLink fieldCode="DE" term="%22QH426-470%22">QH426-470</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Summary: De novo gain-of-function mutations of SCN8A are a significant cause of developmental and epileptic encephalopathy (DEE) (MIM: 614558). The severely affected individuals exhibit refractory seizures, developmental delay, and cognitive disabilities, often accompanied by impaired movement. Individuals with the identical SCN8A variant often differ in clinical course, suggesting a role for modifier genes in disease severity. In a previous study we demonstrated genetic linkage between a hypomorphic mutation in the Gabra2 gene and seizure severity in a mouse model of the human SCN8A pathogenic variant p.Arg1872Trp. Homozygosity for the hypomorphic Gabra2 mutation was associated with early seizure onset and shortened lifespan. We have now confirmed Gabra2 as the modifier gene using a knock-in allele that corrects the splice site variant in strain C57BL/6J. Correction of the Gabra2 variant restores transcript abundance, increases the age of seizure onset, and extends survival of the Scn8a mutant mice. GABRA2 encodes the α2 subunit of the GABAA receptor that provides inhibitory input to dendrites and the the axon initial segment of excitatory neurons. Quantitative variation in human GABAA receptor expression could contribute to variation in the severity of genetic epilepsies and suggests a potential therapeutic intervention.
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: article
– Name: Format
  Label: File Description
  Group: SrcInfo
  Data: electronic resource
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 2666-2477
– Name: NoteTitleSource
  Label: Relation
  Group: SrcInfo
  Data: http://www.sciencedirect.com/science/article/pii/S2666247721000452; https://doaj.org/toc/2666-2477
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1016/j.xhgg.2021.100064
– Name: URL
  Label: Access URL
  Group: URL
  Data: <link linkTarget="URL" linkTerm="https://doaj.org/article/8a7008e3fe9542ceb4f3e110f42a7bd9" linkWindow="_blank">https://doaj.org/article/8a7008e3fe9542ceb4f3e110f42a7bd9</link>
– Name: AN
  Label: Accession Number
  Group: ID
  Data: edsdoj.8a7008e3fe9542ceb4f3e110f42a7bd9
PLink https://login.libproxy.scu.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsdoj&AN=edsdoj.8a7008e3fe9542ceb4f3e110f42a7bd9
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.xhgg.2021.100064
    Languages:
      – Text: English
    Subjects:
      – SubjectFull: Scn8a
        Type: general
      – SubjectFull: Gabra2
        Type: general
      – SubjectFull: epilepsy
        Type: general
      – SubjectFull: epileptic encephalopathy
        Type: general
      – SubjectFull: genetic modifier
        Type: general
      – SubjectFull: voltage-gated sodium channel
        Type: general
      – SubjectFull: Genetics
        Type: general
      – SubjectFull: QH426-470
        Type: general
    Titles:
      – TitleFull: Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Wenxi Yu
      – PersonEntity:
          Name:
            NameFull: Megan K. Mulligan
      – PersonEntity:
          Name:
            NameFull: Robert W. Williams
      – PersonEntity:
          Name:
            NameFull: Miriam H. Meisler
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 01
              Type: published
              Y: 2022
          Identifiers:
            – Type: issn-print
              Value: 26662477
          Numbering:
            – Type: volume
              Value: 3
            – Type: issue
              Value: 1
          Titles:
            – TitleFull: HGG Advances
              Type: main
ResultId 1