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General Information
Name
epilepsy, SCN-alpha-related
FlyBase ID
FBhh0000289
Disease Ontology Term
Parent Disease
OMIM
Overview

This report describes a fly model of epilepsy using alleles of the fly gene para, which encodes a sodium voltage-gated channel alpha subunit. Human voltage-gated sodium channel alpha subunits are encoded by ten different genes, including several associated with forms of epilepsy (SCN1A, SCN2A, SCN8A, SCN9A); these forms of epilepsy exhibit autosomal dominant inheritance. The Dmel\para gene has been extensively characterized; classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

UAS constructs of the human genes Hsap\SCN2A and Hsap\SCN5A have been introduced into flies, but have not been characterized in the context of this disease model. None of the other human genes orthologous to Dmel\para has been introduced into flies.

Mutational lesions of Dmel\para analogous to those found in specific forms of epilepsy have been studied; see "epilepsy, generalized, with febrile seizures plus, type 2" (GEFSP2, FBhh0000309) and "early infantile epileptic encephalopathy 6" (EIEE6, FBhh0000306). Variant(s) implicated in human disease tested (as analogous mutation in fly gene): the endogenous para gene was modified, thus affecting multiple isoforms (corresponds to K1270T in the human SCN1A gene, designated paraGEFS+, implicated in GEFSP2); the endogenous para gene was modified, thus affecting multiple isoforms (corresponds to S1231R in the human SCN1A gene, designated paraDS.S1231R, implicated in EIEE6).

Amorphic alleles of Dmel\para are lethal, usually during larval stages; larvae exhibit neurophysiological defects. Animals carrying homozygous or trans-heterozygous loss-of-function mutations can survive to adulthood; many exhibit heat-sensitive paralysis. Two "bang-sensitive" alleles of this gene (parabss1 and parabss2) are atypical gain-of-function mutations, and were found to have identical mutational lesions. During initial characterization of the disease model, feeding bang-sensitive animals a known anticonvulsant was observed to reduce the intensity and duration of the induced seizures and paralysis significantly; additional pharmaceutical interventions have been tested subsequently. The bang-sensitive phenotype has been used to characterize genetic interactions; see the FlyBase gene report for para.

Several recent studies have shown that different dietary mediums can significantly impact the severity of the para seizure-sensitive phenotypes.

[updated Apr. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: epilepsy, SCN-alpha-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end, to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures are usually associated with progressive dementia. [from Gene Reviews, "SCN1A-Related Seizure Disorders"; pubmed:20301494]

(Note: The following description is for SCN-alpha-related disorders caused specifically by the human gene SCN1A.)

Genetics
Cellular phenotype and pathology
Molecular information
External links
Disease synonyms
Search term: sodium channelopathy
seizure sensitivity
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    paralytic (para) is an essential gene required for locomotor activity. It encodes an α-subunit of voltage-gated sodium channels. It is required for generation of sodium-dependent action potentials. [Date last reviewed: 2019-03-14]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Highest-scoring fly ortholog for human voltage-gated sodium channel alpha subunits encoded by ten different genes, including several associated with forms of epilepsy (SCN1A, SCN2A, SCN8A, SCN9A). Dmel\para shares 44-46% identity and 61-62% similarity with these human genes.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (2 groups)
      RNA-protein
      Interacting group
      Assay
      References
      pull down, anti tag western blot, anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      anti tag coimmunoprecipitation, quantitative reverse transcription pcr
      Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
      Models Based on Experimental Evidence ( 8 )
      Modifiers Based on Experimental Evidence ( 6 )
      Allele
      Disease
      Interaction
      References
      ameliorates  epilepsy
      model of  epilepsy
      model of  epilepsy
      is ameliorated by parats115
      is ameliorated by parats1
      is ameliorated by parabss1
      is exacerbated by paraGEFS+
      is ameliorated by paraGD3392
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - genetic evidence
      PM hybrid dysgenesis
      amorphic allele - genetic evidence
      amorphic allele - genetic evidence
      amorphic allele - genetic evidence
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      phiC31 integrase
      amorphic allele - molecular evidence
      FLPase
      amorphic allele - genetic evidence
      phiC31 integrase
      amorphic allele - genetic evidence
      PM hybrid dysgenesis
      ethyl methanesulfonate
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      amorphic allele - genetic evidence
      ends-out gene targeting
      ends-out gene targeting
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      phiC31 integrase
      References (51)