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General Information
Name
epilepsy, SLC12A5-related
FlyBase ID
FBhh0000296
Disease Ontology Term
Parent Disease
OMIM
Overview

This report describes a fly model of epilepsies that are SLC12A5-related. The human gene implicated in these diseases is SLC12A5, which encodes an integral membrane potassium-chloride transporter. SLC12A5 is implicated in two forms of epilepsy; see OMIM:616645 and OMIM:616685. There is a single fly ortholog, Dmel\kcc, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\kcc is also orthologous to other potassium-chloride cotransporter genes in human (SLC12A4, SLC12A6, and SLC12A7); only SLC12A5 is implicated in epilepsy in humans.

A UAS construct driving the wild-type human gene, Hsap\SLC12A5, has been introduced into flies. Heterologous rescue (functional complementation) of the seizure phenotype of a hypomorphic allele of Dmel\kcc has been observed.

Reduced function of kcc results in seizure sensitivity, including a lowered threshold to evoked electrophysiologically recorded seizure-like activity and "bang-sensitive" phenotypes. Seizure sensitivity is observed in animals with kcc loss-of-function effected by targeted RNAi in either glia or neurons. Amorphic alleles of kcc are lethal. Genetic and physical interactions have been described; see below and in the gene report for kcc.

[updated June 2016 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: epilepsy, SLC12A5-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

(Note: The following description is for one of the two forms of epilepsy for which SLC12A5 is implicated as a causative gene.)

Early infantile epileptic encephalopathy-34 (EIEE34) is an autosomal recessive severe neurologic disorder characterized by onset of refractory migrating focal seizures in infancy. Affected children show developmental regression and are severely impaired globally (summary by Stodberg et al., 2015; pubmed:26333769). [from OMIM:616645; 2016.06.03]

Genetics

EIEE34 is inherited as an autosomal recessive; EIG14 (classified as a susceptibility locus) exhibits autosomal dominant inheritance with incomplete penetrance. [from OMIM:616645; OMIM:616685; 2016.06.03]

Cellular phenotype and pathology
Molecular information

The protein encoded by SLC12A5 is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. [from Gene Cards, SLC12A5; 2016.06.03]

External links
Disease synonyms
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: 4 human to 1 Drosophila; the fly gene kcc is orthologous to SLC12A4, SLC12A5, SLC12A6, and SLC12A7 in human.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    kazachoc (kcc) encodes a potassium:chloride symporter that contributes to seizure susceptibility. [Date last reviewed: 2019-09-12]
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human gene SLC12A4; moderate-scoring ortholog of SLC12A5, SLC12A6, SLC12A7 (1 Drosophila to 4 human). Dmel\kcc shares 51-57% identity and 68-74% similarity with the human genes.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (1 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, peptide massfingerprinting
    Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
    Models Based on Experimental Evidence ( 3 )
    Modifiers Based on Experimental Evidence ( 2 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    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
    Delta2-3 transposase
    amorphic allele - molecular evidence
    ethyl methanesulfonate
    References (11)