Human Disease Model Report: epilepsy, refractory, SCN-alpha-ABCC1 model

General Information

Name

epilepsy, refractory, SCN-alpha-ABCC1 model

FlyBase ID

FBhh0001134

Disease Ontology Term

epilepsy

Parent Disease

OMIM

Overview

A well-studied model of epilepsy in Drosophila makes use of mutant alleles of the fly gene para, which encodes a sodium voltage-gated channel alpha subunit (see 'epilepsy, SCN-alpha-related' FBhh0000289). This model has been used to assess therapeutic pharmaceuticals and drug regimens. A Drosophila model of refractory epilepsy has been created by combining this SCN-alpha-related model of epilepsy with pan-neuronal expression of ABCC1, a human gene involved in multi-drug resistance; ABCC1 (previously MRP1) has been found to be overexpressed in the neurons and glia of patients with refractory epilepsy.

In Drosophila, there is a single high-scoring ortholog of ABCC1, Dmel\MRP; the Drosophila gene has not been used in the context of this disease model.

Pan-neuronal expression of the human gene, Hsap\ABCC1, in the SCN-alpha (Dmel\para) model results in resistance to two antiepileptic drugs tested (sodium phenytoin and valproic acid).

[updated Nov. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: epilepsy, refractory, SCN-alpha-ABCC1 model

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Patients are considered to have refractory epilepsy if disabling seizures continue despite appropriate trials of two antiseizure drugs, either alone or in combination (Engel, 2014; pubmed:24791078).

(FlyBase Curators, 2013-)

Genetics

Cellular phenotype and pathology

Molecular information

ABCC1 (MRP1) has been found to be overexpressed in the neurons and astrocytes of patients with refractory epilepsy (Sun et al., 2016; pubmed:26000815).

(FlyBase Curators, 2013-)

ABCC1 encodes a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra-and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This full transporter is a member of the MRP subfamily which is involved in multi-drug resistance; it functions as a multispecific organic anion transporter. [Gene Cards, ABCC1; 2019.11.05]

(FlyBase Curators, 2013-)

ATP Binding Cassette (ABC) transporters form a special family of membrane proteins, characterized by homologous ATP-binding, and large, multispanning transmembrane domains. Several members of this family are primary active transporters, which significantly modulate the absorption, metabolism, cellular effectivity and toxicity of pharmacological agents (Glavinas et al., 2004; pubmed:16305368).

(FlyBase Curators, 2013-)

The extrusion of anticancer drugs by members of the ATP-binding cassette (ABC) transporter family is one of the most widely recognized mechanisms of multidrug resistance (Fletcher et al., 2016; pubmed:27180306 ).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): ABCC1
Gene Cards: ABCC1
GeneReviews, NCBI Bookshelf: SCN1A-Related Seizure Disorders
MedlinePlus (gene): ABCC1
MARRVEL (human gene): ABCC1
NCBI (Entrez) gene: ABCC1; ATP binding cassette subfamily C member 1 (ABCC1 blood group)

Disease synonyms

Related Diseases

Related human health report(s)

epilepsy

epilepsy, SCN-alpha-related

Ortholog Information

Human gene(s) in FlyBase

Hsap\ABCC1

Human gene (HGNC)

Symbol / Name

ABCC1; ATP binding cassette subfamily C member 1 (ABCC1 blood group)

D. melanogaster ortholog (based on DIOPT)

Dmel\MRP

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human to 1 Drosophila (reciprocal best hits); multiple related genes in both species.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\para

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]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

NAV-A

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

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (3 groups)

para

RNA-protein

Interacting group

Assay

References

para - mle

anti tag coimmunoprecipitation, full identification by RNA sequencing

(Müller et al., 2020)

para - pum

pull down, anti tag western blot, anti tag coimmunoprecipitation, quantitative reverse transcription pcr

(Muraro et al., 2008)

para - Zn72D

anti tag coimmunoprecipitation, quantitative reverse transcription pcr

(Sapiro et al., 2020)

Alleles Reported to Model Human Disease (Disease Ontology) (15 alleles)

para

Models Based on Experimental Evidence ( 12 )

Allele

Disease

Evidence

References

para^HMS00868

model of epilepsy

CEA

(Zhang et al., 2022, Wang et al., 2021)

para^ts115

model of epilepsy

CEA with para^ts1

(Fergestad et al., 2006)

para^ts1

model of epilepsy

CEA

(Fergestad et al., 2006)

CEA with para^ts115

(Fergestad et al., 2006)

para^unspecified

model of epilepsy

CEA

(Kuebler and Tanouye, 2002)

para^GEFS+

model of generalized epilepsy with febrile seizures plus

CEA

(Petruccelli et al., 2015, Sun et al., 2012)

model of Dravet syndrome

CEA

(Schutte et al., 2014)

model of generalized epilepsy with febrile seizures plus 2

CEA

(Mituzaite et al., 2021, Chen et al., 2020)

model of epilepsy

CEA

(Byers et al., 2021)

para^DS.S1231R

model of epilepsy

CEA

(Kaas et al., 2016)

model of Dravet syndrome

CEA

(Mituzaite et al., 2021, Chen et al., 2020, Schutte et al., 2014)

para^Shu

model of epilepsy

CEA

(Chen et al., 2020, Kaas et al., 2016)

para^Shu.UAS

model of epilepsy

CEA

(Kaas et al., 2016)

para^R-C

model of Dravet syndrome

CEA

(Roemmich et al., 2021)

para^R-H

model of generalized epilepsy with febrile seizures plus 2

CEA

(Roemmich et al., 2021)

para^KO.attP

model of epilepsy

CEA

(Tapia et al., 2021)

model of Dravet syndrome

CEA

(Tapia et al., 2021)

Modifiers Based on Experimental Evidence ( 8 )

Allele

Disease

Interaction

References

para^GD3392

ameliorates epilepsy

modeled by para^Shu

(Kaas et al., 2016)

exacerbates developmental and epileptic encephalopathy 64

modeled by RhoBTB^UAS.cSa

(Langhammer et al., 2025)

exacerbates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Al-Ramahi et al., 2018)

para^ts115

ameliorates epilepsy

modeled by para^Shu

(Kaas et al., 2016)

para^KK108534

ameliorates chromosome 16p11.2 deletion syndrome, 593-kb

modeled by CG10465^KK105756

(Iyer et al., 2018)

exacerbates brain cancer

modeled by Ras85D^V12.cUa.UAS, scrib⁶⁷³

(Manzanero-Ortiz et al., 2021)

para^ts1

ameliorates epilepsy

modeled by para^Shu

(Kaas et al., 2016)

model of epilepsy

is exacerbated by Atpα^DTS1

(Fergestad et al., 2006)

para^bss1

model of epilepsy

is ameliorated by shi^{ts1.IVS.p10.20xUAS}

(Kroll et al., 2015)

is ameliorated by Rab9^{Q71L.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by Rab30^{Q66L.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by shi^1.UAS

(Kroll et al., 2015)

is ameliorated by Rab5^{Q88L.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by Rab30^{T21N.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by Rab32^{T33N.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by Rab35^S22N.UAS.YFP

(Kroll et al., 2015)

is ameliorated by shi¹

(Kroll et al., 2015)

is ameliorated by Rab8^{T22N.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by Rab9^{S26N.UASp.YFP}

(Kroll et al., 2015)

is ameliorated by cac^TS2

(Saras and Tanouye, 2016)

is ameliorated by pum^UAS.cSa

(Lin et al., 2017)

is exacerbated by pum^KK109048

(Lin et al., 2017)

is ameliorated by tipE¹

(Parker et al., 2011)

is ameliorated by gish^GD10588

(Howlett et al., 2013)

is exacerbated by chn^KK105251

(Howlett et al., 2013)

is ameliorated by gish⁰⁴⁸⁹⁵

(Howlett et al., 2013)

is ameliorated by kcc^UAS.cHb

(Hekmat-Scafe et al., 2010)

is exacerbated by SLO2^CRISPR

(Byers et al., 2021)

is exacerbated by SLO2^DN.UAS

(Byers et al., 2021)

is ameliorated by Adcy1^rut-1

(Saras and Tanouye, 2016)

is ameliorated by GstS1^M26

(Chen et al., 2020)

ameliorates epilepsy

modeled by para^Shu

(Kaas et al., 2016)

modeled by eas²

(Kroll and Tanouye, 2013)

para^UAS.1-1

exacerbates developmental and epileptic encephalopathy 64

modeled by RhoBTB^UAS.cSa

(Langhammer et al., 2025)

para^GEFS+

exacerbates epilepsy

modeled by para^Shu

(Kaas et al., 2016)

model of epilepsy

is exacerbated by SLO2^CRISPR

(Byers et al., 2021)

is ameliorated by GstS1^M26

(Chen et al., 2020)

para^Shu

model of epilepsy

is ameliorated by para^ts1

(Kaas et al., 2016)

is ameliorated by para^ts115

(Kaas et al., 2016)

is exacerbated by para^GEFS+

(Kaas et al., 2016)

is ameliorated by para^bss1

(Kaas et al., 2016)

is ameliorated by para^GD3392

(Kaas et al., 2016)

is ameliorated by GstS1^GD16335

(Chen et al., 2020)

is ameliorated by GstS1^M26

(Chen et al., 2020)

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

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\ABCC1^UAS.Tag:HA

PBac{UAS-hABCC1.HA}

Hsap\ABCC1^UAS.cBa

P{UAS-MRP1.B}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

para^GD3392

P{GD3392}

w¹¹¹⁸; P{GD3392}v6131

y¹ v¹; P{TRiP.JF01245}attP2/TM3, Sb¹

para^JF01469

P{TRiP.JF01469}

y¹ v¹; P{TRiP.JF01469}attP2

para^HMS00868

P{TRiP.HMS00868}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00868}attP2/TM3, Sb¹

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

para^ko

amorphic allele - molecular evidence

FLPase

para^{MI08578-TG4.0}

amorphic allele - genetic evidence

phiC31 integrase

y¹ w^67c23 Mi{Trojan-GAL4.0}para^{MI08578-TG4.0}/FM7c

para^hd5

amorphic allele - genetic evidence

PM hybrid dysgenesis

para^ts115

ethyl methanesulfonate

para^R-C

CRISPR/Cas9

para^R-H

CRISPR/Cas9

para^KO.attP

amorphic allele - genetic evidence

gene targeting by homologous recombination

para^ts1

ethyl methanesulfonate

para^ts1/C(1)DX, y¹ f¹

para^lk5

amorphic allele - genetic evidence

para^Shu

ethyl methanesulfonate

para^bss1

para^ID30

amorphic allele - genetic evidence

para^lk2

amorphic allele - genetic evidence

para^unspecified

para^GEFS+

ends-out gene targeting

para^DS.S1231R

ends-out gene targeting

para^A

amorphic allele - genetic evidence

ethyl methanesulfonate

y¹ w^* para^A P{neoFRT}19A/FM7c, P{GAL4-Kr.C}DC1, P{UAS-GFP.S65T}DC5, sn⁺

para^B

amorphic allele - genetic evidence

ethyl methanesulfonate

y¹ w^* para^B P{neoFRT}19A/FM7c, P{GAL4-Kr.C}DC1, P{UAS-GFP.S65T}DC5, sn⁺

para^{MI08578-FlpStop.D}

amorphic allele - genetic evidence

phiC31 integrase

y¹ w^* Mi{FlpStop}para^{MI08578-FlpStop.D}/FM7c

References (4)

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