Human Disease Model Report: migraine, familial hemiplegic 2

General Information

Name

migraine, familial hemiplegic 2

FlyBase ID

FBhh0000548

Disease Ontology Term

familial hemiplegic migraine 2

Parent Disease

OMIM

MIGRAINE, FAMILIAL HEMIPLEGIC, 2; FHM2

Overview

This report describes migraine, familial hemiplegic 2 (FHM2); FHM2 exhibits autosomal dominant inheritance. The human gene implicated in FHM2 is ATP1A2, one of multiple sodium/potassium-transporting ATPase alpha subunit genes in human. There is one high-scoring ortholog of ATP1A2 in Drosophila, Atpα, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. ATP1A2 is also implicated in alternating hemiplegia of childhood (MIM:104290). Atpα is orthologous to multiple genes in human; see FBhh0000547.

The human ATP1A2 gene has not been introduced into flies.

Homozygous loss-of-function mutations of Dmel\Atpα are lethal in the embryonic stage. Heterozygous and viable mutant combinations cause stress-sensitivity, temperature-sensitive paralysis, reduced or increased longevity, altered tracheal development, and progressive locomotor defects. Genetic and physical interactions of Dmel\Atpα have been described; see below and in the Atpα gene report.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): A588T in the fly gene Atpα (corresponds to A606T in the human ATP1A2 gene). The A606T missense mutation in human is implicated in FHM2; see Jen, et al., 2007 (pubmed:17435187). The mutation in Drosophila, allele Atpα^CJ13, was isolated based on phenotype and was discovered subsequently to correspond to an ATP1A2 variant implicated in FHM2.

[updated Jun. 2017 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: migraine, familial hemiplegic 2

OMIM report

[MIGRAINE, FAMILIAL HEMIPLEGIC, 2; FHM2](https://omim.org/entry/602481)

Human gene(s) implicated

[ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2](https://omim.org/entry/182340)

Symptoms and phenotype

Unusually severe migraine episodes have been reported in some people with familial hemiplegic migraine. These episodes have included fever, seizures, prolonged weakness, coma, and, rarely, death. Although most people with familial hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months. About 20% of people with this condition develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time, and rapid, involuntary eye movements (nystagmus). [from Genetics Home Reference, familial hemiplegic migraine; 2017.06.05]

(FlyBase Curators, 2013-)

Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. In some types of migraine, including familial hemiplegic migraine, a pattern of neurological symptoms called an aura precedes the headache. [from Genetics Home Reference, familial hemiplegic migraine; 2017.06.05]

(FlyBase Curators, 2013-)

Familial hemiplegic migraine is a subtype of migraine with aura. Migraine is the most common type of chronic, episodic headache. [from MIM:141500, MIM:157300; 2017.06.05]

(OMIM, 2013-)

Genetics

FHM2 is caused by heterozygous mutation in the gene encoding the alpha-2 subunit of the sodium/potassium pump (ATP1A2); autosomal dominant. [from MIM:602481; 2017.06.05]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

See HGNC, Gene Family: ATPase Na+/K+ transporting subunits (ATP1) (http://www.genenames.org/cgi-bin/genefamilies/set/1208).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): ATP1A2
Gene Cards: ATP1A2
GeneReviews, NCBI Bookshelf: Familial Hemiplegic Migraine
MedlinePlus (condition): familial hemiplegic migraine
MedlinePlus (gene): ATP1A2
MARRVEL (human gene): ATP1A2
NCBI MedGen: Familial hemiplegic migraine type 2 (FHM2)
NCBI (Entrez) gene: ATP1A2; ATPase Na+/K+ transporting subunit alpha 2

Disease synonyms

familial basilar migraine

familial hemiplegic migraine

familial hemiplegic migraine 2

FHM2

Related Diseases

Related human health report(s)

neurological disorders, ATPα-related

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

ATP1A2; ATPase Na+/K+ transporting subunit alpha 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Atpα

(DIOPT, 2013-)

Dmel\JYalpha

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many (6 human to 2 Drosophila); orthologous human genes are ATP1A3, ATP1A1, ATP1A2, ATP1A4, ATP4A, ATP12A.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Atpα

Gene Snapshot

Na pump α subunit (Atpα) encodes an integral membrane cation antiporter protein that utilizes ATP to shuttle Na[+] and K[+] across the plasma membrane to maintain ion homeostasis. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

ATPIIC

Comments on ortholog(s)

High-scoring ortholog of human ATP1A3, ATP1A1, and ATP1A2 (with which Dmel\Atpα shares 71-76% identity and 83-86% similarity); moderate-scoring ortholog of ATP1A4, ATP4A, and ATP12A.

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 (29 groups)

Atpα

protein-protein

Interacting group

Assay

References

Atpα - Akt

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Atpα - Chc

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - gig

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Atpα - Hel25E

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ipo9

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Kap-α3

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Karyβ3

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - mats

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

Atpα - Mcad

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Mec2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - MRP

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - nrv2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ost1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ost48

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - OstΔ

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Past1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Rab1

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Scamp

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Sec61α

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - SERCA

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - spidey

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Tctp

pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot

(Lee et al., 2020)

Atpα - Tecr

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Ube3a

enzymatic study, western blot

(Jensen et al., 2013)

Atpα - UQCR-C2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - Vha68-2

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - wal

experimental knowledge based

(Guruharsha et al., 2011)

Atpα - yki

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

Atpα - ZnT63C

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (16 alleles)

Atpα

Models Based on Experimental Evidence ( 16 )

Allele

Disease

Evidence

References

Atpα^HMS00703

model of epilepsy

CEA

(Hope et al., 2020)

Atpα²²⁰⁶

model of nervous system disease

CEA

(Palladino et al., 2003)

Atpα^DTS1

model of nervous system disease

CEA

(Talsma et al., 2014, Fergestad et al., 2006, Palladino et al., 2003)

model of epilepsy

CEA

(Fergestad et al., 2006)

Atpα^DTS1R1

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^DTS2

model of nervous system disease

CEA

(Palladino et al., 2003)

Atpα^CJ5

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

model of nervous system disease

CEA

(Talsma et al., 2014)

Atpα^CJ6

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^CJ7

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^CJ10

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

model of nervous system disease

CEA

(Talsma et al., 2014)

Atpα^CJ13

model of familial hemiplegic migraine

CEA

(Ashmore et al., 2009)

Atpα^I571T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^A576T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^P579T

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^D580F

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^TTTF

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Atpα^mut

model of Charcot-Marie-Tooth disease type 2DD

CEA

(Yuan et al., 2025)

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

Atpα^DTS1

model of nervous system disease

is exacerbated by CG5888^MB00188

(Talsma et al., 2014)

is exacerbated by Cyt-c1L^G9163

(Talsma et al., 2014)

is exacerbated by Dyrk2¹

(Talsma et al., 2014)

is exacerbated by Gαo^MB04922

(Talsma et al., 2014)

is exacerbated by Glt^EY22126

(Talsma et al., 2014)

is exacerbated by Nadk1b^MB05931

(Talsma et al., 2014)

is exacerbated by RpL19^k03704

(Talsma et al., 2014)

is exacerbated by SLO2^MB04544

(Talsma et al., 2014)

is exacerbated by aly¹

(Talsma et al., 2014)

is exacerbated by galectin^DG25505

(Talsma et al., 2014)

is ameliorated by ppk11^MB02012

(Talsma et al., 2014)

is exacerbated by rasp^m47

(Talsma et al., 2014)

is exacerbated by scramb2^EY01180

(Talsma et al., 2014)

exacerbates epilepsy

modeled by eag¹

(Fergestad et al., 2006)

modeled by Sh¹⁴

(Fergestad et al., 2006)

modeled by Sh¹⁴, eag¹

(Fergestad et al., 2006)

modeled by sei¹

(Fergestad et al., 2006)

modeled by para^ts1

(Fergestad et al., 2006)

Atpα^CJ5

model of nervous system disease

is ameliorated by CG5888^MB00188

(Talsma et al., 2014)

is ameliorated by Fkbp59^EY03538

(Talsma et al., 2014)

is ameliorated by Pde1c^c04487

(Talsma et al., 2014)

is ameliorated by Rbp9^Δ1

(Talsma et al., 2014)

is ameliorated by nAChRα6^MB06675

(Talsma et al., 2014)

is ameliorated by ppk11^MB02012

(Talsma et al., 2014)

is ameliorated by rasp^m47

(Talsma et al., 2014)

Atpα^CJ10

model of nervous system disease

is ameliorated by Pu^r1

(Talsma et al., 2014)

is ameliorated by Cyt-c1L^G9163

(Talsma et al., 2014)

is ameliorated by Dyrk2¹

(Talsma et al., 2014)

is ameliorated by Fkbp59^EY03538

(Talsma et al., 2014)

is ameliorated by Gαo^MI00833

(Talsma et al., 2014)

is ameliorated by Sec15²

(Talsma et al., 2014)

is ameliorated by cact⁷

(Talsma et al., 2014)

is ameliorated by pain^EP2451

(Talsma et al., 2014)

is ameliorated by scramb2^EY01180

(Talsma et al., 2014)

is ameliorated by slmb⁰⁰²⁹⁵

(Talsma et al., 2014)

is ameliorated by spz5^e03444

(Talsma et al., 2014)

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

P-type ATPase disorders

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Atpα^GD3093

P{GD3093}

w¹¹¹⁸; P{GD3093}v12330

y¹ v¹; P{TRiP.JF02910}attP2

Atpα^HMS00047

P{TRiP.HMS00047}

y¹ v¹; P{TRiP.HMS00047}attP2/TM3, Sb¹

Atpα^HMS00703

P{TRiP.HMS00703}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00703}attP2

y¹ v¹; P{TRiP.GLC01778}attP40/CyO

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Atpα²²⁰⁶

P-element activity

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

loss of function allele

gamma ray

Atpα^DTS1R2

loss of function allele

gamma ray

Atpα^DTS2R1

loss of function allele

gamma ray

Atpα^DTS2

ethyl methanesulfonate

Atpα^DTS2R3

loss of function allele

gamma ray

Atpα^DTS1

ethyl methanesulfonate

Atpα^CJ5

ethyl methanesulfonate

Atpα^CJ6

ethyl methanesulfonate

Atpα^CJ7

ethyl methanesulfonate

Atpα^CJ10

ethyl methanesulfonate

Atpα^CJ13

ethyl methanesulfonate

References (6)

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