RBCC Red Blood Cell Collection

ATP1A2 (KIAA0778) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Sodium/potassium-transporting ATPase subunit alpha-2; Na(+)/K(+) ATPase alpha-2 subunit; 3.6.3.9 (Sodium pump subunit alpha-2; Flags: Precursor)

hRBCD IPI00003021
IPI00003021 Sodium/potassium-transporting ATPase alpha-2 chain precursor Sodium/potassium-transporting ATPase alpha-2 chain precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight

UniProt P50993
ID AT1A2_HUMAN Reviewed; 1020 AA.
AC P50993; D3DVE4; Q07059; Q5JW74; Q86UZ5; Q9UQ25;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 144.
DE RecName: Full=Sodium/potassium-transporting ATPase subunit alpha-2;
DE Short=Na(+)/K(+) ATPase alpha-2 subunit;
DE EC=3.6.3.9;
DE AltName: Full=Sodium pump subunit alpha-2;
DE Flags: Precursor;
GN Name=ATP1A2; Synonyms=KIAA0778;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2477373;
RA Shull M.M., Pugh D.G., Lingrel J.B.;
RT "Characterization of the human Na,K-ATPase alpha 2 gene and
RT identification of intragenic restriction fragment length
RT polymorphisms.";
RL J. Biol. Chem. 264:17532-17543(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9872452; DOI=10.1093/dnares/5.5.277;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XI.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:277-286(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 211-249.
RC TISSUE=Leukocyte;
RX PubMed=3035563; DOI=10.1073/pnas.84.12.4039;
RA Shull M.M., Lingrel J.B.;
RT "Multiple genes encode the human Na+,K+-ATPase catalytic subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:4039-4043(1987).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 251-442.
RC TISSUE=Brain, and Placenta;
RX PubMed=3036582; DOI=10.1016/0014-5793(87)80677-4;
RA Sverdlov E.D., Monastyrskaya G.S., Broude N.E., Ushkaryov Y.A.,
RA Allikmets R.L., Melkov A.M., Smirnov Y.V., Malyshev I.V.,
RA Dulubova I.E., Petrukhin K.E., Gryshin A.V., Kiyatkin N.I.,
RA Kostina M.B., Sverdlov V.E., Modyanov N.N., Ovchinnikov Y.A.;
RT "The family of human Na+,K+-ATPase genes. No less than five genes
RT and/or pseudogenes related to the alpha-subunit.";
RL FEBS Lett. 217:275-278(1987).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-4.
RX PubMed=2537767; DOI=10.1016/0014-5793(89)80588-5;
RA Sverdlov E.D., Bessarab D.A., Malyshev I.V., Petrukhin K.E.,
RA Smirnov Y.V., Ushkaryov Y.A., Monastyrskaya G.S., Broude N.E.,
RA Modyanov N.N.;
RT "Family of human Na+,K+-ATPase genes. Structure of the putative
RT regulatory region of the alpha+-gene.";
RL FEBS Lett. 244:481-483(1989).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=7711835;
RA Hundal H.S., Maxwell D.L., Ahmed A., Darakhshan F., Mitsumoto Y.,
RA Klip A.;
RT "Subcellular distribution and immunocytochemical localization of Na,K-
RT ATPase subunit isoforms in human skeletal muscle.";
RL Mol. Membr. Biol. 11:255-262(1994).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-570 AND SER-587, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP VARIANTS FHM2 GLN-689 AND THR-731.
RX PubMed=12953268; DOI=10.1002/ana.10674;
RA Vanmolkot K.R.J., Kors E.E., Hottenga J.-J., Terwindt G.M., Haan J.,
RA Hoefnagels W.A.J., Black D.F., Sandkuijl L.A., Frants R.R.,
RA Ferrari M.D., van den Maagdenberg A.M.J.M.;
RT "Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated
RT with familial hemiplegic migraine and benign familial infantile
RT convulsions.";
RL Ann. Neurol. 54:360-366(2003).
RN [12]
RP VARIANTS FHM2 PRO-764 AND ARG-887, AND CHARACTERIZATION OF VARIANTS
RP FMH2 PRO-764 AND ARG-887.
RX PubMed=12539047; DOI=10.1038/ng1081;
RA De Fusco M., Marconi R., Silvestri L., Atorino L., Rampoldi L.,
RA Morgante L., Ballabio A., Aridon P., Casari G.;
RT "Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit
RT associated with familial hemiplegic migraine type 2.";
RL Nat. Genet. 33:192-196(2003).
RN [13]
RP VARIANT AHC1 ASN-378.
RX PubMed=15174025; DOI=10.1002/ana.20134;
RA Swoboda K.J., Kanavakis E., Xaidara A., Johnson J.E., Leppert M.F.,
RA Schlesinger-Massart M.B., Ptacek L.J., Silver K., Youroukos S.;
RT "Alternating hemiplegia of childhood or familial hemiplegic migraine?
RT A novel ATP1A2 mutation.";
RL Ann. Neurol. 55:884-887(2004).
RN [14]
RP VARIANT FHM2 ARG-715.
RX PubMed=21352219; DOI=10.1111/j.1526-4610.2010.01793.x;
RA De Sanctis S., Grieco G.S., Breda L., Casali C., Nozzi M.,
RA Del Torto M., Chiarelli F., Verrotti A.;
RT "Prolonged sporadic hemiplegic migraine associated with a novel de
RT novo missense ATP1A2 gene mutation.";
RL Headache 51:447-450(2011).
RN [15]
RP VARIANT FHM2 TRP-1007.
RX PubMed=23838748; DOI=10.1177/0333102413495116;
RA Pisano T., Spiller S., Mei D., Guerrini R., Cianchetti C.,
RA Friedrich T., Pruna D.;
RT "Functional characterization of a novel C-terminal ATP1A2 mutation
RT causing hemiplegic migraine and epilepsy.";
RL Cephalalgia 33:1302-1310(2013).
RN [16]
RP VARIANT FHM2 SER-874.
RX PubMed=23918834; DOI=10.1177/0333102413498941;
RA Costa C., Prontera P., Sarchielli P., Tonelli A., Bassi M.T.,
RA Cupini L.M., Caproni S., Siliquini S., Donti E., Calabresi P.;
RT "A novel ATP1A2 gene mutation in familial hemiplegic migraine and
RT epilepsy.";
RL Cephalalgia 0:0-0(2013).
CC -!- FUNCTION: This is the catalytic component of the active enzyme,
CC which catalyzes the hydrolysis of ATP coupled with the exchange of
CC sodium and potassium ions across the plasma membrane. This action
CC creates the electrochemical gradient of sodium and potassium,
CC providing the energy for active transport of various nutrients.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O + Na(+)(In) + K(+)(Out) = ADP +
CC phosphate + Na(+)(Out) + K(+)(In).
CC -!- SUBUNIT: Composed of three subunits: alpha (catalytic), beta and
CC gamma.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. Cell
CC membrane; Multi-pass membrane protein.
CC -!- DISEASE: Migraine, familial hemiplegic, 2 (FHM2) [MIM:602481]: A
CC subtype of migraine with aura associated with hemiparesis in some
CC families. Migraine is a disabling symptom complex of periodic
CC headaches, usually temporal and unilateral. Headaches are often
CC accompanied by irritability, nausea, vomiting and photophobia,
CC preceded by constriction of the cranial arteries. Migraine with
CC aura is characterized by recurrent attacks of reversible
CC neurological symptoms (aura) that precede or accompany the
CC headache. Aura may include a combination of sensory disturbances,
CC such as blurred vision, hallucinations, vertigo, numbness and
CC difficulty in concentrating and speaking. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Alternating hemiplegia of childhood 1 (AHC1)
CC [MIM:104290]: A rare syndrome of episodic hemi- or quadriplegia
CC lasting minutes to days. Most cases are accompanied by dystonic
CC posturing, choreoathetoid movements, nystagmus, other ocular motor
CC abnormalities, autonomic disturbances, and progressive cognitive
CC impairment. It is typically distinguished from familial hemiplegic
CC migraine by infantile onset and high prevalence of associated
CC neurological deficits that become increasingly obvious with age.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type)
CC (TC 3.A.3) family. Type IIC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA34498.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATP1A2";
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DR EMBL; J05096; AAA51797.1; -; Genomic_DNA.
DR EMBL; AB018321; BAA34498.2; ALT_INIT; mRNA.
DR EMBL; AL121987; CAI15271.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52740.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52741.1; -; Genomic_DNA.
DR EMBL; BC052271; AAH52271.2; -; mRNA.
DR EMBL; M16795; AAA51799.1; -; mRNA.
DR EMBL; M27578; AAA35575.1; -; Genomic_DNA.
DR EMBL; M27571; AAA35575.1; JOINED; Genomic_DNA.
DR EMBL; M27576; AAA35575.1; JOINED; Genomic_DNA.
DR EMBL; Y07494; CAA68793.1; ALT_SEQ; mRNA.
DR PIR; A34474; A34474.
DR RefSeq; NP_000693.1; NM_000702.3.
DR UniGene; Hs.34114; -.
DR ProteinModelPortal; P50993; -.
DR SMR; P50993; 25-1020.
DR IntAct; P50993; 1.
DR STRING; 9606.ENSP00000354490; -.
DR BindingDB; P50993; -.
DR ChEMBL; CHEMBL2095186; -.
DR TCDB; 3.A.3.1.1; the p-type atpase (p-atpase) superfamily.
DR PhosphoSite; P50993; -.
DR DMDM; 1703467; -.
DR PaxDb; P50993; -.
DR PRIDE; P50993; -.
DR Ensembl; ENST00000361216; ENSP00000354490; ENSG00000018625.
DR GeneID; 477; -.
DR KEGG; hsa:477; -.
DR UCSC; uc001fvb.2; human.
DR CTD; 477; -.
DR GeneCards; GC01P160085; -.
DR HGNC; HGNC:800; ATP1A2.
DR HPA; CAB022230; -.
DR MIM; 104290; phenotype.
DR MIM; 182340; gene.
DR MIM; 602481; phenotype.
DR neXtProt; NX_P50993; -.
DR Orphanet; 2131; Alternating hemiplegia of childhood.
DR Orphanet; 569; Familial or sporadic hemiplegic migraine.
DR PharmGKB; PA30796; -.
DR eggNOG; COG0474; -.
DR HOGENOM; HOG000265622; -.
DR HOVERGEN; HBG004298; -.
DR InParanoid; P50993; -.
DR KO; K01539; -.
DR OMA; IINIPLP; -.
DR OrthoDB; EOG7327N0; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; ATP1A2; human.
DR GeneWiki; ATP1A2; -.
DR GenomeRNAi; 477; -.
DR NextBio; 1977; -.
DR PRO; PR:P50993; -.
DR ArrayExpress; P50993; -.
DR Bgee; P50993; -.
DR CleanEx; HS_ATP1A2; -.
DR Genevestigator; P50993; -.
DR GO; GO:0005901; C:caveola; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0005768; C:endosome; IEA:Ensembl.
DR GO; GO:0005890; C:sodium:potassium-exchanging ATPase complex; IC:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:Ensembl.
DR GO; GO:0030315; C:T-tubule; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005391; F:sodium:potassium-exchanging ATPase activity; IMP:UniProtKB.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0006754; P:ATP biosynthetic process; IEA:InterPro.
DR GO; GO:0015991; P:ATP hydrolysis coupled proton transport; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0040011; P:locomotion; IEA:Ensembl.
DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; IEA:Ensembl.
DR GO; GO:0045822; P:negative regulation of heart contraction; IEA:Ensembl.
DR GO; GO:0045988; P:negative regulation of striated muscle contraction; IEA:Ensembl.
DR GO; GO:0001504; P:neurotransmitter uptake; IEA:Ensembl.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:0086004; P:regulation of cardiac muscle cell contraction; IEA:Ensembl.
DR GO; GO:0002087; P:regulation of respiratory gaseous exchange by neurological system process; IEA:Ensembl.
DR GO; GO:0006940; P:regulation of smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0006942; P:regulation of striated muscle contraction; NAS:UniProtKB.
DR GO; GO:0002026; P:regulation of the force of heart contraction; IEA:Ensembl.
DR GO; GO:0019229; P:regulation of vasoconstriction; IEA:Ensembl.
DR GO; GO:0035094; P:response to nicotine; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR Gene3D; 1.20.1110.10; -; 2.
DR Gene3D; 2.70.150.10; -; 2.
DR Gene3D; 3.40.1110.10; -; 1.
DR InterPro; IPR006068; ATPase_P-typ_cation-transptr_C.
DR InterPro; IPR004014; ATPase_P-typ_cation-transptr_N.
DR InterPro; IPR023299; ATPase_P-typ_cyto_domN.
DR InterPro; IPR005775; ATPase_P-typ_Na/K_IIC.
DR InterPro; IPR018303; ATPase_P-typ_P_site.
DR InterPro; IPR023298; ATPase_P-typ_TM_dom.
DR InterPro; IPR008250; ATPase_P-typ_transduc_dom_A.
DR InterPro; IPR001757; Cation_transp_P_typ_ATPase.
DR InterPro; IPR023214; HAD-like_dom.
DR Pfam; PF00689; Cation_ATPase_C; 1.
DR Pfam; PF00690; Cation_ATPase_N; 1.
DR Pfam; PF00122; E1-E2_ATPase; 1.
DR Pfam; PF00702; Hydrolase; 1.
DR PRINTS; PR00119; CATATPASE.
DR SMART; SM00831; Cation_ATPase_N; 1.
DR SUPFAM; SSF56784; SSF56784; 2.
DR SUPFAM; SSF81660; SSF81660; 1.
DR TIGRFAMs; TIGR01106; ATPase-IIC_X-K; 1.
DR TIGRFAMs; TIGR01494; ATPase_P-type; 2.
DR PROSITE; PS00154; ATPASE_E1_E2; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Complete proteome; Disease mutation;
KW Hydrolase; Ion transport; Magnesium; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Potassium; Potassium transport;
KW Reference proteome; Sodium; Sodium transport;
KW Sodium/potassium transport; Transmembrane; Transmembrane helix;
KW Transport.
FT PROPEP 1 5 By similarity.
FT /FTId=PRO_0000002503.
FT CHAIN 6 1020 Sodium/potassium-transporting ATPase
FT subunit alpha-2.
FT /FTId=PRO_0000002504.
FT TOPO_DOM 6 85 Cytoplasmic (Potential).
FT TRANSMEM 86 106 Helical; (Potential).
FT TOPO_DOM 107 129 Extracellular (Potential).
FT TRANSMEM 130 150 Helical; (Potential).
FT TOPO_DOM 151 286 Cytoplasmic (Potential).
FT TRANSMEM 287 306 Helical; (Potential).
FT TOPO_DOM 307 318 Extracellular (Potential).
FT TRANSMEM 319 336 Helical; (Potential).
FT TOPO_DOM 337 769 Cytoplasmic (Potential).
FT TRANSMEM 770 789 Helical; (Potential).
FT TOPO_DOM 790 799 Extracellular (Potential).
FT TRANSMEM 800 820 Helical; (Potential).
FT TOPO_DOM 821 840 Cytoplasmic (Potential).
FT TRANSMEM 841 863 Helical; (Potential).
FT TOPO_DOM 864 915 Extracellular (Potential).
FT TRANSMEM 916 935 Helical; (Potential).
FT TOPO_DOM 936 948 Cytoplasmic (Potential).
FT TRANSMEM 949 967 Helical; (Potential).
FT TOPO_DOM 968 982 Extracellular (Potential).
FT TRANSMEM 983 1003 Helical; (Potential).
FT TOPO_DOM 1004 1020 Cytoplasmic (Potential).
FT REGION 80 82 Interaction with phosphoinositide-3
FT kinase (By similarity).
FT ACT_SITE 374 374 4-aspartylphosphate intermediate (By
FT similarity).
FT METAL 714 714 Magnesium (By similarity).
FT METAL 718 718 Magnesium (By similarity).
FT MOD_RES 570 570 Phosphothreonine.
FT MOD_RES 587 587 Phosphoserine.
FT MOD_RES 940 940 Phosphoserine; by PKA (By similarity).
FT VARIANT 378 378 T -> N (in AHC1; dbSNP:rs28934002).
FT /FTId=VAR_019934.
FT VARIANT 689 689 R -> Q (in FHM2; dbSNP:rs28933401).
FT /FTId=VAR_019935.
FT VARIANT 715 715 G -> R (in FHM2; de novo mutation in a
FT sporadic case).
FT /FTId=VAR_065685.
FT VARIANT 731 731 M -> T (in FHM2; dbSNP:rs28933400).
FT /FTId=VAR_019936.
FT VARIANT 764 764 L -> P (in FHM2; loss of function;
FT dbSNP:rs28933398).
FT /FTId=VAR_019937.
FT VARIANT 874 874 G -> S (in FHM2; some patients exhibit a
FT clinical overlap between migraine and
FT epilepsy).
FT /FTId=VAR_069991.
FT VARIANT 887 887 W -> R (in FHM2; loss of function;
FT dbSNP:rs28933399).
FT /FTId=VAR_019938.
FT VARIANT 1007 1007 R -> W (in FHM2; some patients exhibit a
FT clinical overlap between migraine and
FT epilepsy).
FT /FTId=VAR_069992.
SQ SEQUENCE 1020 AA; 112265 MW; AFBD8EA94FFB4FC3 CRC64;
MGRGAGREYS PAATTAENGG GKKKQKEKEL DELKKEVAMD DHKLSLDELG RKYQVDLSKG
LTNQRAQDVL ARDGPNALTP PPTTPEWVKF CRQLFGGFSI LLWIGAILCF LAYGIQAAME
DEPSNDNLYL GVVLAAVVIV TGCFSYYQEA KSSKIMDSFK NMVPQQALVI REGEKMQINA
EEVVVGDLVE VKGGDRVPAD LRIISSHGCK VDNSSLTGES EPQTRSPEFT HENPLETRNI
CFFSTNCVEG TARGIVIATG DRTVMGRIAT LASGLEVGRT PIAMEIEHFI QLITGVAVFL
GVSFFVLSLI LGYSWLEAVI FLIGIIVANV PEGLLATVTV CLTLTAKRMA RKNCLVKNLE
AVETLGSTST ICSDKTGTLT QNRMTVAHMW FDNQIHEADT TEDQSGATFD KRSPTWTALS
RIAGLCNRAV FKAGQENISV SKRDTAGDAS ESALLKCIEL SCGSVRKMRD RNPKVAEIPF
NSTNKYQLSI HEREDSPQSH VLVMKGAPER ILDRCSTILV QGKEIPLDKE MQDAFQNAYM
ELGGLGERVL GFCQLNLPSG KFPRGFKFDT DELNFPTEKL CFVGLMSMID PPRAAVPDAV
GKCRSAGIKV IMVTGDHPIT AKAIAKGVGI ISEGNETVED IAARLNIPMS QVNPREAKAC
VVHGSDLKDM TSEQLDEILK NHTEIVFART SPQQKLIIVE GCQRQGAIVA VTGDGVNDSP
ALKKADIGIA MGISGSDVSK QAADMILLDD NFASIVTGVE EGRLIFDNLK KSIAYTLTSN
IPEITPFLLF IIANIPLPLG TVTILCIDLG TDMVPAISLA YEAAESDIMK RQPRNSQTDK
LVNERLISMA YGQIGMIQAL GGFFTYFVIL AENGFLPSRL LGIRLDWDDR TMNDLEDSYG
QEWTYEQRKV VEFTCHTAFF ASIVVVQWAD LIICKTRRNS VFQQGMKNKI LIFGLLEETA
LAAFLSYCPG MGVALRMYPL KVTWWFCAFP YSLLIFIYDE VRKLILRRYP GGWVEKETYY
//

MIM 104290
*RECORD*
*FIELD* NO
104290
*FIELD* TI
#104290 ALTERNATING HEMIPLEGIA OF CHILDHOOD 1; AHC1
*FIELD* TX
A number sign (#) is used with this entry because alternating hemiplegia
read moreof childhood-1 (AHC1) is caused by heterozygous mutation in the ATP1A2
gene (182340) on chromosome 1q.

Familial hemiplegic migraine-2 (FHM2; 602481) is an allelic disorder
with some overlapping features.

DESCRIPTION

Alternating hemiplegia of childhood is a rare syndrome of episodic hemi-
or quadriplegia lasting minutes to days. Most cases are accompanied by
dystonic posturing, choreoathetoid movements, nystagmus, other ocular
motor abnormalities, autonomic disturbances, and progressive cognitive
impairment (Mikati et al., 1992).

The disorder may mimic or overlap with other disorders, including
familial hemiplegic migraine (FHM1; 141500) and GLUT1 deficiency
syndrome (606777) (Rotstein et al., 2009).

- Genetic Heterogeneity of Alternating Hemiplegia of Childhood

See also AHC2 (614820), caused by mutation in the ATP1A3 gene (182350).

CLINICAL FEATURES

Mikati et al. (1992) reported what appeared to be the first instance of
familial occurrence of alternating hemiplegia of childhood. Inheritance
appeared to be autosomal dominant. The proband, a 9-year-old boy,
presented with developmental retardation, rare tonic-clonic seizures and
frequent episodes of flaccid alternating hemiplegia that had been
presumed to represent postictal paralysis. The hemiplegia spells, which
started in his first year, did not respond to multiple antiepileptics.
Between attacks, there was choreoathetosis and dystonic posturing. A
brother, the father, a paternal uncle, and the maternal grandmother had
similar histories of alternating hemiplegia. Investigations included
negative CT and metabolic studies. EEG and SPECT scanning failed to
reveal any significant slowing or major changes in cortical perfusion
during hemiplegia as compared with nonhemiplegic periods. The karyotype
demonstrated a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34)
in the patient, in all the affected living relatives, and in 1
apparently unaffected sib. The asymptomatic mother had a normal
karyotype. Both affected sibs were treated with and responded to
flunarizine, a calcium-entry blocker, with a greater than 70% decrease
in attack frequency.

Among a group of 22 presumably unrelated patients with alternating
hemiplegia of childhood, Bourgeois et al. (1993) described onset before
18 months of age, repeated episodes of hemiplegia lasting from a few
minutes to several days, the occurrence of tonic or dystonic attacks,
nystagmus, dyspnea, cognitive impairment, and choreoathetosis. All of
the patients also had episodes of quadriplegia that occurred either when
a hemiplegia was shifting from one side to the other or as an isolated
phenomenon. Six patients also had epileptic seizures, but Bourgeois et
al. (1993) considered the 2 disorders to be distinct. Treatment with
flunarizine was partially effective.

Kramer et al. (2000) reported 2 half sisters with alternating hemiplegia
of childhood who had the same mother and different fathers. The authors
ruled out mitochondrial abnormalities and suggested autosomal dominant
inheritance.

Kanavakis et al. (2003) reported a family with alternating hemiplegia of
childhood inherited in an autosomal dominant pattern. The proband was a
9-year-old boy with mental retardation, tonic-clonic seizures, dystonic
attacks, and episodes of alternating hemiplegia starting at age 2.5
years. His mother, 3 brothers, and maternal uncle had similar symptoms.
Other clinical features included autonomic changes in affected limbs and
abnormal extraocular movements. Brain imaging, cytogenetic analysis, and
mitochondrial DNA analysis were normal. Headache was not a feature.
Flunarizine treatment reduced the severity of episodes.

MOLECULAR GENETICS

In affected members of the family reported by Kanavakis et al. (2003),
Swoboda et al. (2004) identified a thr378-to-asn mutation in the ATP1A2
gene (T378N; 182340.0005). Mutation analysis in 8 sporadic patients and
affected subjects from 5 additional kindreds with alternating hemiplegia
of childhood did not identify additional mutations in the ATP1A2 gene.

In 4 affected members of a Greek family with alternating hemiplegia of
childhood, Bassi et al. (2004) identified the T378N mutation in the
ATP1A2 gene. Mutation analysis of the ATP1A2 gene in 10 sporadic
patients was negative.

*FIELD* RF
1. Bassi, M. T.; Bresolin, N.; Tonelli, A.; Nazos, K.; Crippa, F.;
Baschirotto, C.; Zucca, C.; Bersano, A.; Dolcetta, D.; Boneschi, F.
M.; Barone, V.; Casari, G.: A novel mutation in the ATP1A2 gene causes
alternating hemiplegia of childhood. J. Med. Genet. 41: 621-628,
2004.

2. Bourgeois, M.; Aicardi, J.; Goutieres, F.: Alternating hemiplegia
of childhood. J. Pediat. 122: 673-679, 1993.

3. Kanavakis, E.; Xaidara, A.; Papathanasiou-Klontza, D.; Papadimitiou,
A.; Velentza, A.; Youroukos, S.: Alternating hemiplegia of childhood:
a syndrome inherited with an autosomal dominant trait. Dev. Med.
Child Neurol. 45: 833-836, 2003. Note: Erratum: Dev. Med. Child Neurol.
46: 288 only, 2004.

4. Kramer, U.; Nevo, Y.; Margalit, D.; Shorer, Z.; Harel, S.: Alternating
hemiplegia of childhood in half-sisters. J. Child Neurol. 15: 128-130,
2000.

5. Mikati, M. A.; Maguire, H.; Barlow, C. F.; Ozelius, L.; Breakefield,
X. O.; Klauck, S. M.; Korf, B.; O'Tuama, S. L. A.; Dangond, F.: A
syndrome of autosomal dominant alternating hemiplegia: clinical presentation
mimicking intractable epilepsy; chromosomal studies; and physiologic
investigations. Neurology 42: 2251-2257, 1992.

6. Rotstein, M.; Doran, J.; Yang, H.; Ullner, P. M.; Engelstad, K.;
De Vivo, D. C.: GLUT1 deficiency and alternating hemiplegia of childhood. Neurology 73:
2042-2044, 2009.

7. Swoboda, K. J.; Kanavakis, E.; Xaidara, A.; Johnson, J. E.; Leppert,
M. F.; Schlesinger-Massart, M. B.; Ptacek, L. J.; Silver, K.; Youroukos,
S.: Alternating hemiplegia of childhood or familial hemiplegic migraine?:
a novel ATP1A2 mutation. Ann. Neurol. 55: 884-887, 2004.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Abnormal extraocular movements;
Nystagmus;
Upward eye deviation during episodes

NEUROLOGIC:
[Central nervous system];
Hemiplegia, episodic;
Quadriplegia, episodic;
Cognitive decline, progressive;
Mental retardation;
Dystonia;
Choreoathetosis;
Autonomic involvement affecting limbs during episodes;
Generalized tonic-clonic seizures in 50%;
Neurologic regression after prolonged episodes;
Headache is usually not a symptom

MISCELLANEOUS:
Onset before 18 months of age;
Favorable response to flunarizine;
Familial hemiplegic migraine-2 (FHM2, 602481) is an allelic disorder
with an overlapping phenotype

MOLECULAR BASIS:
Caused by mutation in the ATPase, Na+K+ transporting, alpha-2 polypeptide
gene (ATP1A2, 182340.0005)

*FIELD* CD
Cassandra L. Kniffin: 8/4/2004

*FIELD* ED
joanna: 08/19/2004
ckniffin: 8/4/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 1/24/2011
Marla J. F. O'Neill - updated: 11/3/2004
Cassandra L. Kniffin - updated: 8/4/2004

*FIELD* CD
Victor A. McKusick: 3/16/1994

*FIELD* ED
carol: 09/14/2012
ckniffin: 9/13/2012
wwang: 2/17/2011
ckniffin: 1/24/2011
tkritzer: 11/11/2004
tkritzer: 11/4/2004
terry: 11/3/2004
tkritzer: 8/10/2004
ckniffin: 8/4/2004
carol: 3/16/1994

MIM 182340
*RECORD*
*FIELD* NO
182340
*FIELD* TI
*182340 ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2
;;SODIUM-POTASSIUM-ATPase, ALPHA-2 POLYPEPTIDE;;
read moreNa,K-ATPase, ALPHA-A(+) CATALYTIC POLYPEPTIDE;;
Na,K-ATPase, ALPHA-B POLYPEPTIDE
*FIELD* TX

DESCRIPTION

The ATP1A2 gene encodes the alpha-2 isoform of the Na(+),K(+)-ATPase (EC
3.6.1.9), an integral membrane protein responsible for establishing and
maintaining the electrochemical gradients of Na and K ions across the
plasma membrane. The pump is composed of 2 subunits, a large catalytic
subunit (alpha), encoded by several genes (see, e.g., ATP1A1; 182310),
and a smaller glycoprotein subunit (beta) (see ATP1B1; 182330) (summary
by Shull and Lingrel, 1987).

CLONING

Shull and Lingrel (1987) identified separate genes encoding the alpha
and alpha(+) isoforms of the catalytic subunit of the Na(+),K(+)-ATPase.
These genes were called alpha-A (ATP1A1) and alpha-B (ATP1A2),
respectively. In addition, they isolated 2 other genes, termed alpha-C
(ATP1A3; 182350) and alpha-D (ATP1A4; 670321), one of which is
physically linked to the alpha-B gene; these genes showed nucleotide and
deduced amino acid homology to the catalytic subunit cDNA sequences, but
did not correspond to any previously identified isoforms.

Shull et al. (1989) cloned the ATP1A2 gene. The amino acid sequence
deduced from the genomic sequence exhibited 99% identity to the rat
alpha-2 isoform. Several transcription factor binding sites are located
in the 5-prime end of the gene.

The alpha-2 subunit consists of 10 transmembrane helices M1-M10,
harboring the Na(+) and K(+)-binding sites, and a cytoplasmic head made
up of 3 subdomains: A (actuator), N (nucleotide binding), and P
(phosphorylation) (summary by Schack et al., 2012).

GENE STRUCTURE

Shull et al. (1989) determined that the ATP1A2 gene contains 23 exons
and spans approximately 25 kb.

GENE FUNCTION

Katzmarzyk et al. (1999) examined the relationship between the ATP1A2
(exon 1 and exon 21-22 with BglII) and ATP1B1 (182330) (MspI and PvuII)
genes and resting metabolic rate (RMR) and respiratory quotient (RQ).
RMR and RQ were adjusted for age, sex, fat mass, and fat-free mass.
Sib-pair analyses indicated a significant linkage between RQ and the
ATP1A2 exon 1 and exon 21-22 markers (P of 0.03 and 0.02, respectively).
No linkage was detected between the ATP1B1 markers and either RMR or RQ,
and RMR was not linked with the ATP1A2 markers. There was a significant
interaction (p less than 0.0003) between ATP1A2 exon 1 carrier status
and age group (younger adults (those less than 45 years old) vs older
adults (those 45 or more years old)) for RQ. The association between
carrier status and RQ was significant in younger adults (RQ of 0.76 in
carriers vs 0.80 in noncarriers; p less than 0.0001) but was not in
older adults (RQ of 0.81 in carriers vs 0.80 in noncarriers). The ATP1A2
exon 1 gene accounted for approximately 9.1% and 0.3% of the variance in
RQ in younger and older adults, respectively. The results suggested that
the ATP1A2 gene may play a role in fuel oxidation, particularly in
younger individuals.

To determine the functional roles of the ATP1A1 and ATP1A2 proteins,
James et al. (1999) generated mice with a targeted disruption of either
the Atp1a1 or the Atp1a2 gene. Hearts from heterozygous Atp1a2 mice were
hypercontractile as a result of increased calcium transients during the
contractile cycle. In contrast, hearts from heterozygous Atp1a1 mice
were hypocontractile. The different functional roles of these 2 proteins
were further demonstrated since inhibition of the Atp1a2 protein with
ouabain increased the contractility of heterozygous Atp1a1 hearts. These
results illustrated a specific role for the ATP1A2 protein in calcium
signaling during cardiac contraction.

MAPPING

By Southern analysis of DNA from panels of rodent/human somatic cell
hybrid lines, Yang-Feng et al. (1988) mapped the ATP1A2 gene to
1cen-q32. Furthermore, they detected a common Pst1 RFLP with the ATP1A2
probe. In the course of creating a physical map of human 1q21-q23, Oakey
et al. (1992) confirmed this assignment.

BIOCHEMICAL FEATURES

- Crystal Structure

Morth et al. (2007) presented the x-ray crystal structure at
3.5-angstrom resolution of the pig renal sodium-potassium-ATPase
(Na+,K(+)-ATPase) with 2 rubidium ions bound (as potassium congeners) in
an occluded state in the transmembrane part of the alpha subunit.
Several of the residues forming the cavity for rubidium/potassium
occlusion in the Na+,K(+)-ATPase are homologous to those binding calcium
in the calcium-ion ATPase of sarcoendoplasmic reticulum (SERCA1;
108730). The beta (see ATP1B1, 182330) and gamma (see ATP1G1, 601814)
subunits specific to the Na+,K(+)-ATPase are associated with
transmembrane helices alpha-M7/alpha-M10, and alpha-M9, respectively.
The gamma subunit corresponds to a fragment of the V-type ATPase c
subunit. The carboxy terminus of the alpha subunit is contained within a
pocket between transmembrane helices and seems to be a novel regulatory
element controlling sodium affinity, possibly influenced by the membrane
potential.

Crystal structures of the potassium-bound form of the sodium potassium
ATPase pump revealed an intimate docking of the alpha-subunit carboxy
terminus at the transmembrane domain (e.g., Morth et al., 2007). Poulsen
et al. (2010) showed that this element is a key regulator of a
theretofore unrecognized ion pathway. Models of P-type ATPases operated
with a single ion conduit through the pump, but the data of Poulsen et
al. (2010) suggested an additional pathway in the Na+/K(+)-ATPase
between the ion-binding sites and the cytoplasm. The C-terminal pathway
allows a cytoplasmic proton to enter and stabilize site III when empty
in the potassium-bound state, and when potassium is released the proton
will also return to the cytoplasm, thus allowing an overall asymmetric
stoichiometry of the transported ions. The C terminus controls the gate
to the pathway. Its structure is crucial for pump function, as
demonstrated by at least 8 mutations in the region that cause severe
neurologic diseases. This novel model for ion transport by the
Na+/K(+)-ATPase was established by electrophysiologic studies of
C-terminal mutations in familial hemiplegic migraine (602481) and was
further substantiated by molecular dynamics simulations. Poulsen et al.
(2010) considered a similar ion regulation likely to apply to the
H+/K(+)-ATPase and the Ca(2+)-ATPase.

MOLECULAR GENETICS

In affected members of a large Italian family segregating familial
hemiplegic migraine-2 (FHM2; 602481), De Fusco et al. (2003) identified
heterozygosity for mutations in the ATP1A2 gene
(182340.0001-182340.0002).

In affected members of a family with alternating hemiplegia of
childhood-1 (AHC1; 104290), Swoboda et al. (2004) identified a mutation
in the ATP1A2 gene (182340.0006).

Jurkat-Rott et al. (2004) identified 6 different mutations in the ATP1A2
gene (see, e.g., 182340.0008; 182340.0009) in affected members of 6
unrelated families with FHM2. Penetrance was mildly reduced at
approximately 87%.

Vanmolkot et al. (2007) reported an affected family in which the proband
with severe FHM2 was compound heterozygous for 2 mutations in the ATP1A2
gene (182340.0011; 182340.0012). Family members with milder forms of the
disorder were heterozygous for 1 of the mutations, suggesting reduced
penetrance. The authors stated that this was the first report of
compound heterozygosity in FHM2.

Schack et al. (2012) reported functional analysis of 9 different
pathogenic mutations in the ATP1A2 gene, including 4 in the P domain
(M731T (182340.0003), R593W, V628M, and E700K), 2 in the A domain (R202Q
and T263M), 1 in the transmembrane domain M2 (V138A), 1 in transmembrane
M4 domain near the P domain (T345A; 182340.0007), and 1 between M6 and
M7 close to the P domain (R834Q). Expression of the mutations in COS-1
cells showed that all had reductions in the catalytic turnover rate of
Na+ and K+. The decrease was most severe for R593W, V628M, M731T, and
R834Q (less than one-third of wildtype), about 50% for T263M, T345A,
E700K, and V138A, and less than 20% of control for R202Q. All mutants
showed essentially normal affinity for K+ and Na+, but rapid kinetic
studies of the phosphorylation from ATP showed reduced Vmax of
phosphorylation as a major factor contributing to the reduction of the
catalytic turnover rate of mutants V138A, T345A, R593W, V628M, M731T,
and R834Q (2- to 6-fold decrease). The decreased phosphorylation rate
would lead to enhanced K+ competition with Na+ at intracellular sites,
which would compromise pump function. E700K, R202Q, and T263M
phosphorylation rates were similar to wildtype, but E700K showed
impaired rates of dephosphorylation, and R202Q and T263M were predicted
to affect the turnover rate of the E1P/E2P pump conformations. Overall,
the findings suggested that the disturbance of clearance of
extracellular K+ by glial cells, thought to underlie FHM2, is due to low
turnover rate of the pump and not to decreased affinity of the pump for
external K+.

ANIMAL MODEL

Ashmore et al. (2009) identified 6 different EMS-induced missense
mutations in the Atp1a2 and Atp1a3 (182350) genes in Drosophila. All
mutations resulted in reduced respiration activity consistent with a
loss of ATPase function and a hypomorphic effect. Different mutant
strains exhibited some abnormalities, including progressive
temperature-dependent paralysis, progressive stress-sensitive paralysis,
and decreased locomotor activity in response to startle, suggesting a
decrease in maximal locomotion capacity. Neuromuscular studies showed
allele-specific pathology, including brain vacuoles and myopathology,
and biochemical studies showed decreased metabolic rates. An unexpected
finding was the some mutant strains had increased longevity, which was
not related to caloric restriction. Low doses of ouabain showed a
similar effect on longevity in control groups. Ashmore et al. (2009)
suggested that these findings may be relevant for studying the
pathogenesis of FHM2 and DYT12 (128235).

*FIELD* AV
.0001
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, LEU764PRO

In a large Italian family with familial hemiplegic migraine-2 (602481),
De Fusco et al. (2003) identified a heterozygous 2395T-C mutation in the
ATP1A2 gene, resulting in a leu764-to-pro (L764P) substitution. The
mutation segregated with the disorder in all 22 affected members who
were tested and was not present in 400 control chromosomes. Functional
studies in HeLa cells showed that the L764P and W887R (182340.0002)
mutations inhibited Na+/K+ pump activity, but did not affect assembly or
translocation to the cell membrane. Resultant abnormalities in intra-
and extracellular ion concentrations may contribute to the
pathophysiology of the disorder.

.0002
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, TRP887ARG

In a family with familial hemiplegic migraine-2 (602481), De Fusco et
al. (2003) identified a heterozygous 2763T-C mutation in the ATP1A2
gene, resulting in a trp887-to-arg (W887R) substitution. The mutation
segregated with the disorder in all 7 affected members and was not
present in 400 control chromosomes. Also see 182340.0001.

.0003
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, MET731THR

In affected members of a family with familial hemiplegic migraine-2
(602481), Vanmolkot et al. (2003) identified a heterozygous 2296T-C
transition in exon 16 of the ATP1A2 gene, resulting in a met731-to-thr
(M731T) substitution.

Segall et al. (2005) found that the mutant M731T and R689Q (182340.0004)
rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic
turnover and increased apparent affinity for extracellular potassium. In
addition, M731T showed an increased apparent affinity for ATP. Segall et
al. (2005) suggested that the disease phenotype is caused by decreased
activity of the Na+/K+ pump, resulting in delayed extracellular
potassium clearance and/or altered localized calcium handling or
signaling.

Castro et al. (2007) identified the M731T mutation in 3 affected members
of a Portuguese family with FHM2. A fourth mutation carrier had only
migraine with aura.

Schack et al. (2012) noted that the M731T mutation occurs in the P
domain. Expression of the mutation in COS-1 cells showed a severe
reduction in the catalytic turnover rate of Na+ and K+, which was due to
reduced Vmax of phosphorylation. The mutant showed essentially normal
affinity for K+ and Na+. The decreased phosphorylation rate would lead
to enhanced K+ competition with Na+ at intracellular sites, which would
compromise pump function. The findings suggested that the disturbance of
clearance of extracellular K+ by glial cells, thought to underlie FHM2,
is due to low turnover rate of the pump and not to decreased affinity of
the pump for external K+.

.0004
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, ARG689GLN

In affected members of a family with familial hemiplegic migraine-2
(602481) previously reported by Terwindt et al. (1997), Vanmolkot et al.
(2003) identified a 2170G-A transition in exon 15 of the ATP1A2 gene,
resulting in an arg689-to-gln (R689Q) substitution. Three individuals
with the mutation and FHM also had benign familial infantile convulsions
(BFIC), 1 member had the mutation and only BFIC, and 2 members had the
mutation and only migraine with or without aura. The authors noted that
this family expanded the clinical features of the phenotype caused by
mutation in the ATP1A2 gene.

Segall et al. (2005) found that the mutant R689Q and M731T (182340.0003)
rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic
turnover and increased apparent affinity for extracellular potassium.
Segall et al. (2005) suggested that the disease phenotype is caused by
decreased activity of the Na+/K+ pump, resulting in delayed
extracellular potassium clearance and/or altered localized calcium
handling or signaling.

.0005
ALTERNATING HEMIPLEGIA OF CHILDHOOD 1
ATP1A2, THR378ASN

In affected members of a family with alternating hemiplegia of
childhood-1 (AHC1; 104290) originally reported by Kanavakis et al.
(2003), Swoboda et al. (2004) identified a 1237C-A transversion in exon
9 of the ATP1A2 gene, resulting in a thr378-to-asn (T378N) substitution.
The mutation affects a highly conserved residue in the second
cytoplasmic loop of the protein and was not identified in 382 control
chromosomes.

In 4 affected members of a Greek family with alternating hemiplegia of
childhood, Bassi et al. (2004) identified the T378N mutation. The
mutation was not present in unaffected members of the family or in 250
control chromosomes.

.0006
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, GLY301ARG

In affected members of an Italian family with severe familial hemiplegic
migraine-2 (602481), Spadaro et al. (2004) identified a 901G-A
transition in the ATP1A2 gene, resulting in a gly301-to-arg (G301R)
substitution. The mutation occurs in a highly conserved residue within
transmembrane segment M3 of the protein that is important for the
dephosphorylation of homologous ATPases. The mutation was not identified
in 179 controls.

.0007
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, THR345ALA

In affected members of a Finnish family with familial hemiplegic
migraine-2 (602481) with associated symptoms such as coma and showing
linkage to 1q23, Kaunisto et al. (2004) identified a 1033A-G transition
in exon 9 of the ATP1A2 gene, resulting in a thr345-to-ala (T345A)
substitution. All 11 affected members in this family showed hemisensoric
aura with mild to moderate hemiparesis affecting mostly the arm.
Interictal neurologic examinations were normal. Migraine attacks usually
started with gradually spreading hemisensoric aura which was always
accompanied by hemiparesthesias, dysarthria, or dysphagia, and often by
visual symptoms. Of the 11 affected family members, 10 reported onset
before the age of 15 years. The frequency of attacks varied from 2 per
month to once a year, and 2 individuals reported cessation of attacks
during their teens. Minor head trauma triggered attacks in 5 of the 11
patients and severe vomiting could last for days in 4 patients.
Confusion and mild anxiety were common features during attacks in 5
subjects. In 4 of these patients a mild head trauma had triggered coma
accompanied by fever that lasted 2 days to 2 weeks. Hemiparetic symptoms
could persist for as long as 2 weeks in some individuals. None of the
patients had seizures.

In functional expression studies, Segall et al. (2004) found that cells
transduced with the T345A mutant protein showed growth comparable to
wildtype cells and no reduction in catalytic turnover of the subunit
protein; however, kinetic studies showed that the T345A mutant protein
had an approximately 2-fold decrease in apparent affinity for
extracellular potassium. The authors concluded that the slow removal of
potassium from the extracellular space slowed the recovery phase of
nerve impulse transmission.

Schack et al. (2012) noted that the T345A mutation occurs in the M4
transmembrane domain near the P domain. Expression of the mutation in
COS-1 cells showed about a 50% reduction in the catalytic turnover rate
of Na+ and K+, which was due to reduced Vmax of phosphorylation. The
mutant showed essentially normal affinity for K+ and Na+. The decreased
phosphorylation rate would lead to enhanced K+ competition with Na+ at
intracellular sites, which would compromise pump function. The findings
suggested that the disturbance of clearance of extracellular K+ by glial
cells, thought to underlie FHM2, is due to low turnover rate of the pump
and not to decreased affinity of the pump for external K+.

.0008
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, ASP718ASN

In 6 affected members spanning 4 generations of a family with FHM2
(602481), Jurkat-Rott et al. (2004) identified a heterozygous 2152G-A
transition in the ATP1A2 gene, resulting in an asp718-to-asn (D718N)
substitution. Age at onset ranged from 3 to 12 years, and hemiplegic
episodes were long, lasting from 6 to 336 hours. In most patients, the
frequency of attacks ranged from 1 to 2 episodes per month. Aural
features included dysarthria, diplopia, and impaired hearing. One
patient was mentally retarded and had epileptic seizures, and another
had low IQ. The D718N mutation affects a magnesium-interaction site and
is predicted to result in complete loss of ATPase function due to lack
of catalytic activity.

.0009
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, PRO979LEU

In 5 affected members of a family with FHM2 (602481), Jurkat-Rott et al.
(2004) identified a heterozygous 2936C-T transition in the ATP1A2 gene,
resulting in a pro979-to-leu (P979L) substitution. Age at onset ranged
from 3 to 23 years, and hemiplegic attacks occurred several times per
year. One patient had mental retardation, and another had epileptic
seizures.

.0010
MIGRAINE, FAMILIAL BASILAR
ATP1A2, ARG548HIS

In a father and son (proband) with basilar migraine (see 602481),
Ambrosini et al. (2005) identified a heterozygous 1643G-A transition in
exon 12 of the ATP1A2 gene, resulting in an arg548-to-his (R548H)
substitution in a highly conserved region of the protein. Residue 548
occurs in the major alpha-2 subunit cytoplasmic loop, which plays a key
role in pump function. The mutation was not identified in 400 control
chromosomes. The R548H mutation was also identified in the proband's
paternal uncle who had basilar migraines in his youth, but at the time
of the report had migraine without aura, and in the proband's first
cousin, who had migraine without aura. Ambrosini et al. (2005) concluded
that basilar migraine is allelic to FHM2.

.0011
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, ILE286THR

In a young woman with severe hemiplegic migraine (602481), Vanmolkot et
al. (2007) identified compound heterozygosity for 2 mutations in the
ATP1A2 gene: a 961T-C transition in exon 8, resulting in an
ile286-to-thr (I286T) substitution, and a 1348C-T transition in exon 10,
resulting in a thr415-to-met (T415M; 182340.0012) substitution, both of
which are located in the intracellular portion of the protein. The
patient had onset at age 8 years of hemiplegic migraine with visual aura
and subsequent dysphasia, hemiplegia, and migraine headache. Her mother
and maternal aunt, both of whom were heterozygous for the I286T
mutation, had aura without headache and a milder form of hemiplegic
migraine, respectively. In vitro functional expression studies showed
that the I286T mutant protein was expressed but caused significantly
decreased cell survival that reflected a dysfunctional pump. Her
unaffected daughter was heterozygous for the T415M mutation, as were her
father and son, who had nonmigrainous headaches and migraine with aura,
respectively. In vitro functional expression studies showed that the
T415M mutant protein was expressed, but cells with the mutant protein
were unable to survive, indicating complete loss of function. Vanmolkot
et al. (2007) noted that this was the first reported case of compound
heterozygosity for mutations in the ATP1A2 gene and concluded that the
mutations showed reduced penetrance in the heterozygous state.

.0012
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, THR415MET

See 182340.0011 and Vanmolkot et al. (2007).

.0013
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, ARG65TRP

In 3 affected members of a family with FHM2 (602481), Tonelli et al.
(2007) identified a heterozygous 193C-T transition in exon 4 of the
ATP1A2 gene, resulting in an arg65-to-trp (R65W) substitution in the
cytoplasmic N-terminal portion of the protein, within the actuator
domain (A domain).

.0014
MIGRAINE, FAMILIAL HEMIPLEGIC, 2
ATP1A2, THR376MET

In affected members of a Portuguese family with pure FHM2 (602481),
Castro et al. (2007) identified a heterozygous 1231C-T transition in
exon 9 of the ATP1A2 gene, resulting in a thr376-to-met (T376M)
substitution in the M4 cytoplasmic loop. In vitro functional expression
studies showed that the mutant protein had decreased function.

*FIELD* RF
1. Ambrosini, A.; D'Onofrio, M.; Grieco, G. S.; Di Mambro, A.; Montagna,
G.; Fortini, D.; Nicoletti, F.; Nappi, G.; Sances, G.; Schoenen, J.;
Buzzi, M. G.; Santorelli, F. M.; Pierelli, F.: Familial basilar migraine
associated with a new mutation in the ATP1A2 gene. Neurology 66:
1826-1828, 2005.

2. Ashmore, L. J.; Hrizo, S. L.; Paul, S. M.; Van Voorhies, W. A.;
Beitel, G. J.; Palladino, M. J.: Novel mutations affecting the Na,
K ATPase alpha model complex neurological diseases and implicate the
sodium pump in increased longevity. Hum. Genet. 126: 431-447, 2009.

3. Bassi, M. T.; Bresolin, N.; Tonelli, A.; Nazos, K.; Crippa, F.;
Baschirotto, C.; Zucca, C.; Bersano, A.; Dolcetta, D.; Boneschi, F.
M.; Barone, V.; Casari, G.: A novel mutation in the ATP1A2 gene causes
alternating hemiplegia of childhood. J. Med. Genet. 41: 621-628,
2004.

4. Castro, M.-J.; Stam, A. H.; Lemos, C.; Barros, J.; Gouveia, R.
G.; Martins, I. P.; Koenderink, J. B.; Vanmolkot, K. R. J.; Mendes,
A. P.; Frants, R. R.; Ferrari, M. D.; Sequeiros, J.; Pereira-Monteiro,
J. M.; van den Maagdenberg, A. M. J. M.: Recurrent ATP1A2 mutations
in Portuguese families with familial hemiplegic migraine. J. Hum.
Genet. 52: 990-998, 2007.

5. De Fusco, M.; Marconi, R.; Silvestri, L.; Atorino, L.; Rampoldi,
L.; Morgante, L.; Ballabio, A.; Aridon, P.; Casari, G.: Haploinsufficiency
of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with
familial hemiplegic migraine type 2. Nature Genet. 33: 192-196,
2003.

6. James, P. F.; Grupp, I. L.; Grupp, G.; Woo, A. L.; Askew, G. R.;
Croyle, M. L.; Walsh, R. A.; Lingrel, J. B.: Identification of a
specific role for the Na,K-ATPase alpha-2 isoform as a regulator of
calcium in the heart. Molec. Cell 3: 555-563, 1999.

7. Jurkat-Rott, K.; Freilinger, T.; Dreier, J. P.; Herzog, J.; Gobel,
H.; Petzold, G. C.; Montagna, P.; Gasser, T.; Lehmann-Horn, F.; Dichgans,
M.: Variability of familial hemiplegic migraine with novel A1A2 Na(+)/K(+)-ATPase
variants. Neurology 62: 1857-1861, 2004.

8. Kanavakis, E.; Xaidara, A.; Papathanasiou-Klontza, D.; Papadimitriou,
A.; Velentza, S.; Youroukos, S.: Alternating hemiplegia of childhood:
a syndrome inherited with an autosomal dominant trait. Dev. Med.
Child Neurol. 45: 833-836, 2003. Note: Erratum: Dev. Med. Child Neurol.
46: 288 only, 2004.

9. Katzmarzyk, P. T.; Rankinen, T.; Perusse, L.; Deriaz, O.; Tremblay,
A.; Borecki, I.; Rao, D. C.; Bouchard, C.: Linkage and association
of the sodium potassium-adenosine triphosphatase alpha-2 and beta-1
genes with respiratory quotient and resting metabolic rate in the
Quebec Family Study. J. Clin. Endocr. Metab. 84: 2093-2097, 1999.

10. Kaunisto, M. A.; Harno, H.; Vanmolkot, K. R. J.; Gargus, J. J.;
Sun, G.; Hamalainen, E.; Liukkonen, E.; Kallela, M.; van den Maagdenberg,
A. M. J. M.; Frants, R. R.; Farkkila, M.; Palotie, A.; Wessman, M.
: A novel missense ATP1A2 mutation in a Finnish family with familial
hemiplegic migraine type 2. Neurogenetics 5: 141-146, 2004.

11. Morth, J. P.; Pedersen, B. P.; Toustrup-Jensen, M. S.; Sorensen,
T. L.-M.; Petersen, J.; Andersen, J. P.; Vilsen, B.; Nissen, P.:
Crystal structure of the sodium-potassium pump. Nature 450: 1043-1049,
2007.

12. Oakey, R. J.; Watson, M. L.; Seldin, M. F.: Construction of a
physical map on mouse and human chromosome 1: comparison of 13 Mb
of mouse and 11 Mb of human DNA. Hum. Molec. Genet. 1: 613-620,
1992.

13. Poulsen, H.; Khandelia, H.; Morth, J. P.; Bublitz, M.; Mouritsen,
O. G.; Egebjerg, J.; Nissen, P.: Neurological disease mutations compromise
a C-terminal ion pathway in the Na+/K+-ATPase. Nature 467: 99-102,
2010.

14. Schack, V. R.; Holm, R.; Vilsen, B.: Inhibition of phosphorylation
of Na+,K+-ATPase by mutations causing familial hemiplegic migraine. J.
Biol. Chem. 287: 2191-2202, 2012.

15. Segall, L.; Mezzetti, A.; Scanzano, R.; Gargus, J. J.; Purisima,
E.; Blostein, R.: Alterations in the alpha-2 isoform of Na,K-ATPase
associated with familial hemiplegic migraine type 2. Proc. Nat. Acad.
Sci. 102: 11106-11111, 2005.

16. Segall, L.; Scanzano, R.; Kaunisto, M. A.; Wessman, M.; Palotie,
A.; Gargus, J. J.; Blostein, R.: Kinetic alterations due to a missense
mutation in the Na,K-ATPase alpha-2 subunit cause familial hemiplegic
migraine type 2. J. Biol. Chem. 279: 43692-43696, 2004.

17. Shull, M. M.; Lingrel, J. B.: Multiple genes encode the human
Na+,K+-ATPase catalytic subunit. Proc. Nat. Acad. Sci. 84: 4039-4043,
1987.

18. Shull, M. M.; Pugh, D. G.; Lingrel, J. B.: Characterization of
the human Na,K-ATPase alpha 2 gene and identification of intragenic
restriction fragment length polymorphisms. J. Biol. Chem. 264: 17532-17543,
1989.

19. Spadaro, M.; Ursu, S.; Lehmann-Horn, F.; Veneziano, L.; Antonini,
G.; Giunti, P.; Frontali, M.; Jurkat-Rott, K.: A G301R Na+/K+-ATPase
mutation causes familial hemiplegic migraine type 2 with cerebellar
signs. Neurogenetics 5: 177-185, 2004. Note: Erratum: Neurogenetics
6: 169 only, 2005.

20. Swoboda, K. J.; Kanavakis, E.; Xaidara, A.; Johnson, J. E.; Leppert,
M. F.; Schlesinger-Massart, M. B.; Ptacek, L. J.; Silver, K.; Youroukos,
S.: Alternating hemiplegia of childhood or familial hemiplegic migraine?:
a novel ATP1A2 mutation. Ann. Neurol. 55: 884-887, 2004.

21. Terwindt, G. M.; Ophoff, R. A.; Lindhout, D.; Haan, J.; Halley,
D. J.; Sandkuijl, L. A.; Brouwer, O. F.; Frants, R. R.; Ferrari, M.
D.: Partial cosegregation of familial hemiplegic migraine and a benign
familial infantile epileptic syndrome. Epilepsia 38: 915-921, 1997.

22. Tonelli, A.; Gallanti, A.; Bersano, A.; Cardin, V.; Ballabio,
E.; Airoldi, G.; Redaelli, F.; Candelise, L.; Bresolin, N.; Bassi,
M. T.: Amino acid changes in the amino terminus of the Na,K-adenosine
triphosphatase alpha-2 subunit associated to familial and sporadic
hemiplegic migraine. Clin. Genet. 72: 516-523, 2007.

23. Vanmolkot, K. R. J.; Kors, E. E.; Hottenga, J.-J.; Terwindt, G.
M.; Haan, J.; Hoefnagels, W. A. J.; Black, D. F.; Sandkuijl, L. A.;
Frants, R. R.; Ferrari, M. D.; van den Maagdenberg, A. M. J. M.:
Novel mutations in the Na+,K+-ATPase pump gene ATP1A2 associated with
familial hemiplegic migraine and benign familial infantile convulsions. Ann.
Neurol. 54: 360-366, 2003.

24. Vanmolkot, K. R. J.; Stam, A. H.; Raman, A.; Koenderink, J. B.;
de Vries, B.; van den Boogerd, E. H.; van Vark, J.; van den Heuvel,
J. J. M. W.; Bajaj, N.; Terwindt, G. M.; Haan, J.; Frants, R. R.;
Ferrari, M. D.; van den Maagdenberg, A. M. J. M.: First case of compound
heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine. Europ.
J. Hum. Genet. 15: 884-888, 2007.

25. Yang-Feng, T. L.; Schneider, J. W.; Lindgren, V.; Shull, M. M.;
Benz, E. J., Jr.; Lingrel, J. B.; Francke, U.: Chromosomal localization
of human Na+,K+-ATPase alpha- and beta-subunit genes. Genomics 2:
128-138, 1988.

*FIELD* CN
Cassandra L. Kniffin - updated: 11/7/2012
Ada Hamosh - updated: 9/27/2010
Cassandra L. Kniffin - updated: 5/24/2010
Cassandra L. Kniffin - updated: 5/6/2008
Cassandra L. Kniffin - updated: 1/10/2008
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - updated: 10/10/2006
Cassandra L. Kniffin - updated: 4/7/2006
Cassandra L. Kniffin - updated: 3/9/2005
Cassandra L. Kniffin - updated: 1/13/2005
Victor A. McKusick - updated: 12/29/2004
Marla J. F. O'Neill - updated: 11/3/2004
Cassandra L. Kniffin - updated: 10/25/2004
Cassandra L. Kniffin - updated: 8/4/2004
Cassandra L. Kniffin - updated: 12/30/2003
Cassandra L. Kniffin - updated: 1/24/2003
John A. Phillips, III - updated: 3/3/2000
Stylianos E. Antonarakis - updated: 7/20/1999

*FIELD* CD
Victor A. McKusick: 12/1/1987

*FIELD* ED
terry: 11/09/2012
carol: 11/9/2012
ckniffin: 11/7/2012
carol: 9/14/2012
ckniffin: 9/13/2012
alopez: 9/28/2010
terry: 9/27/2010
wwang: 5/25/2010
ckniffin: 5/24/2010
wwang: 5/14/2008
ckniffin: 5/6/2008
carol: 1/21/2008
ckniffin: 1/10/2008
wwang: 8/24/2007
ckniffin: 8/16/2007
wwang: 10/17/2006
ckniffin: 10/10/2006
wwang: 4/11/2006
ckniffin: 4/7/2006
wwang: 11/23/2005
ckniffin: 11/14/2005
wwang: 3/16/2005
wwang: 3/10/2005
ckniffin: 3/9/2005
tkritzer: 1/25/2005
ckniffin: 1/13/2005
tkritzer: 12/30/2004
terry: 12/29/2004
tkritzer: 11/4/2004
terry: 11/3/2004
tkritzer: 10/28/2004
ckniffin: 10/25/2004
ckniffin: 8/4/2004
tkritzer: 1/16/2004
ckniffin: 12/30/2003
alopez: 1/31/2003
carol: 1/30/2003
cwells: 1/28/2003
ckniffin: 1/24/2003
mgross: 3/3/2000
mgross: 7/21/1999
mgross: 7/20/1999
carol: 2/9/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 7/8/1988
marie: 3/25/1988

MIM 602481
*RECORD*
*FIELD* NO
602481
*FIELD* TI
#602481 MIGRAINE, FAMILIAL HEMIPLEGIC, 2; FHM2
;;MHP2
MIGRAINE, FAMILIAL BASILAR, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because familial hemiplegic
migraine-2 (FHM2) and familial basilar migraine are caused by
heterozygous mutation in the gene encoding the alpha-2 subunit of the
sodium/potassium pump (ATP1A2; 182340) on chromosome 1q23.

Alternating hemiplegia of childhood (104290) is an allelic disorder with
an overlapping phenotype.

For a phenotypic description and a discussion of genetic heterogeneity
of familial hemiplegic migraine, see FHM1 (141500).

CLINICAL FEATURES

Echenne et al. (1999) reported a boy who experienced recurrent comas
precipitated by hemiparesis or paresthesias, aphasia, headaches, and
behavioral changes, with subsequent loss of consciousness. A history of
migraine or hemiplegic migraine was found in several family members.
Linkage to chromosome 1q21-q23 was found.

Marconi et al. (2003) reported 2 Italian families with autosomal
dominant familial hemiplegic migraine. One large family had multiple
affected members over 6 generations. Clinical features of the 2 families
were similar, with age at onset in the first or second decade (range, 2
to 18 years), migraine with aura, visual disturbances, language
disturbances (dysarthria, dysphasia), hemiparesis, hemiparesthesias, and
often confusion. Five patients had seizures, and 3 patients in the large
family had mild to moderate mental retardation.

Vanmolkot et al. (2003) reported a Dutch family in which 5 members in 3
generations were affected with familial hemiplegic migraine, each with a
somewhat different clinical phenotype. The proband, a 33-year-old woman,
had onset at age 3 years of headache accompanied by one-sided sensory
symptoms, weakness in one arm, and transient speech disturbances. Total
attack duration was 1 to 2 days, with a frequency of twice a year to
bimonthly. Her mother and grandmother were both affected from ages 7 and
9 years, respectively, until menarche (age 16 years in both) with
headache with aura, and hand or arm weakness for 1 to 2 days. An uncle
of the proband had attacks of aura without headache, with speech
difficulties, sensory symptoms, and unilateral loss of hand control.
Finally, a cousin of the proband had attacks with headache with aura,
sensory symptoms, and weakness in arm and face.

Spadaro et al. (2004) reported an Italian family in which 8 members
spanning 3 generations had FHM2. Onset for all patients was before 30
years of age, and 6 patients had severe neurologic involvement with
alterations of consciousness and fever. Frequency of attacks ranged from
1 per month to 1 per year and typically lasted for several days. The
proband was a 28-year-old woman who had migraine with visual aura since
age 8 years. Beginning at age 12 years, she had several episodes of
tonic-clonic seizures followed by elevated temperature and coma.
Subsequently, she had hemiparesis, global aphasia, and cerebellar
deficits, including nystagmus, dysarthria, dysmetria, gait ataxia, and
intention tremor. During coma, CT scans showed diffuse swelling of the
brain and EEG showed diffuse slow delta and theta activity that returned
to normal in 2 weeks. Her mother had episodes of migraine with aura
often associated with hemiparesis or hemihypoasthesia. Confusion,
aphasia, fever, and cerebellar signs also occurred. The proband's
72-year-old grandmother had a similar history of hemiplegic migraines
and was the only patient to show residual interictal cerebellar signs.
Spadaro et al. (2004) noted that cerebellar involvement had not
previously been associated with FHM2.

Jurkat-Rott et al. (2004) reported 6 unrelated families with FHM2.
Unusual aura symptoms included dysarthria, diplopia, alien limb
phenomenon, impaired hearing, and vertigo. Triggering factors included
exercise, heat, emotional stress, head trauma, and angiography.

Dreier et al. (2005) reported a 29-year-old man who developed a fever,
right-sided hemiplegia, aphasia, and coma over the course of several
days triggered by exertional heat stroke. Approximately 24 hours after
symptom onset, T1-weighted MRI studies showed evidence of a mild but
significant left hemispheric blood-brain barrier opening limited to the
cortex and preceding cortical edema. The findings suggested that the
delayed cortical edema was vasogenic in this patient, and Dreier et al.
(2005) suggested a link with the theory of cortical spreading depression
in migraine aura. After a medical history suggested FHM, genetic
analysis identified a mutation in the ATP1A2 gene, consistent with FHM2.

Vanmolkot et al. (2006) reported a Dutch family with FHM2 confirmed by
genetic analysis. At age 2 years, the proband had 2 episodes of
transient blindness, restlessness, and fever that were triggered by head
trauma. After the second episode, she showed developmental regression
and autistic behavior; at age 8 years she had permanent mild mental
retardation. Family history revealed several other affected members who
were diagnosed retrospectively with hemiplegic migraine and confusional
migraine.

Vanmolkot et al. (2007) reported a young woman with severe hemiplegic
migraine who was found to be compound heterozygous for 2 mutations in
the ATP1A2 gene (I286T; 182340.0011 and T415M; 182340.0012). The patient
had onset at age 8 years of typical hemiplegic migraine with visual aura
and subsequent dysphasia, hemiplegia, and migraine headache. Her mother
and maternal aunt, both of whom were heterozygous for the I286T
mutation, had aura without headache and a milder form of hemiplegic
migraine, respectively. Her unaffected daughter was heterozygous for the
T415M mutation, as were her father and son, who had nonmigrainous
headaches and migraine with aura, respectively.

Castro et al. (2008) reported 2 Portuguese families with FHM2 in which
some affected individuals had features consistent with borderline
personality disorder and mental retardation, respectively.

Riant et al. (2010) identified putative pathogenic de novo mutations in
the ATP1A2 gene in 11 (44%) of 25 patients with onset of sporadic
hemiplegic migraine before age 16 years. Four had pure hemiplegic
migraine, 5 had seizures, and 5 had developmental delay or learning
disabilities at school. Two patients experiences episodes of
unconsciousness or prolonged coma. None had permanent cerebellar ataxia.
Among the remaining patients with sporadic disease, 8 (32%) had de novo
mutations in the CACNA1A gene (601011), resulting in an overall mutation
frequency of 76% among patients with early-onset sporadic hemiplegic
migraine. Overall, the phenotype was more severe in patients with
CACNA1A mutations.

- Familial Basilar Migraine

Basilar migraine is a subtype of migraine with aura in which the aura
symptoms originate from the brainstem or reflect the simultaneous
involvement of both hemispheres. Ambrosini et al. (2005) reported a son
and his father with basilar migraine who were found to have a
heterozygous mutation in the ATP1A2 gene (182340.0010). Age at onset was
15 and 12 years, respectively. Aura was characterized by scintillating
scotomas, paraesthesias and hypoesthesias in the arms and perioral
region, dysarthria, bilateral tinnitus, and vertigo. Typical migraine
symptoms of headache, nausea, vomiting, yawning, and photo- and
phonophobia started soon after resolution of the aura. The ATP1A2
mutation was also identified in the proband's paternal uncle who had
basilar migraines in his youth, but at the time of the report had
migraine without aura, and in the proband's first cousin, who had
migraine without aura. Ambrosini et al. (2005) concluded that basilar
migraine is allelic to FHM2.

MAPPING

- Familial Hemiplegic Migraine

In a large French pedigree with FHM, Ducros et al. (1997) excluded
linkage of the disorder to the MHP1 locus on chromosome 19 and found
linkage to chromosome 1q21-q23. Linkage to chromosome 1 was confirmed in
2 other families, but linkage to both chromosome 1 and chromosome 19 was
excluded in 4 families. Chromosome 1-linked families differed from
chromosome 19-linked families in that penetrance was much lower in the
former, and in some of the affected members, epileptic seizures occurred
during severe migraine attacks.

In a large Italian family with FHM, Marconi et al. (2003) narrowed the
critical region of FHM2 to a 0.9 Mb area on chromosome 1q23 between
markers D1S2635 and CASQ1-SNP. All affected members of the family shared
a common haplotype.

- Typical Migraine Susceptibility

In a study of Australian twins with familial typical migraine, Nyholt et
al. (2005) obtained a lod score of 1.53 on chromosome 1 at 159 cM using
regression analysis. This peak was within 3 cM of the FHM-implicated
ATP1A2 gene, thus potentially implicating this gene in familial typical
migraine. By subphenotype analyses, they found indications that
individual symptoms were differentially associated with particular
linkage peaks in their data. Specifically, 5 of the 10 International
Headache Society (IHS) symptoms produced nominally significant lod
scores at the chromosome 1 locus, with 'nausea/vomiting' and
'phonophobia' being the symptoms most associated. In a subphenotype
analysis for each symptom, in which affected individuals must simply
have the individual symptom, regardless of latent-class analysis (LCA)
diagnosis, the chromosome 1 locus was most associated with phonophobia
(lod = 1.79).

MOLECULAR GENETICS

In a large Italian family with autosomal dominant familial hemiplegic
migraine spanning 6 generations, De Fusco et al. (2003) identified a
point mutation in the ATP1A2 gene (182340.0001). In a second family with
7 affected members, De Fusco et al. (2003) identified a different point
mutation in the ATP1A2 gene (182340.0002). Functional data indicated
that the putative pathogenetic mechanism is triggered by the loss of
function of a single allele. The authors suggested that 2 synergistic
events may occur as a result of a mutation: an increase in extracellular
potassium, producing a wide cortical depolarization and an increase in
intracellular potassium, which may promote an increase in intracellular
calcium through the sodium/calcium exchanger. An increase in
intracellular calcium would resemble the effect of CACNA1A (601011)
mutations that cause FHM1.

In all affected members of a Dutch family with FHM2, Vanmolkot et al.
(2003) identified a heterozygous mutation in the ATP1A2 gene
(182340.0003).

In affected members of a large Dutch-Canadian family reported by
Terwindt et al. (1997) in which FHM and benign familial infantile
convulsions (BFIC) partially cosegregated over 5 generations, Vanmolkot
et al. (2003) identified a mutation in the ATP1A2 gene (182340.0004). Of
the patients for whom genetic information was available, 3 with the
mutation had FHM and BFIC, 5 with the mutation had FHM without BFIC, 1
with the mutation had only BFIC, and 2 with the mutation had only
migraine with or without aura. Several other members with migraines did
not have the mutation.

In affected members of an Italian family with severe FHM2, Spadaro et
al. (2004) identified a mutation in the ATP1A2 gene (182340.0006).

Jurkat-Rott et al. (2004) identified 6 different mutations in the ATP1A2
gene (see, e.g., 182340.0008; 182340.0009) in affected members of 6
unrelated families with FHM2. Penetrance was mildly reduced at
approximately 87%.

Vanmolkot et al. (2007) reported an affected family in which the proband
with severe FHM2 was compound heterozygous for 2 mutations in the ATP1A2
gene (182340.0011; 182340.0012). Family members with milder forms of the
disorder were heterozygous for 1 of the mutations, suggesting reduced
penetrance. The authors stated that this was the first report of
compound heterozygosity in FHM2.

De Vries et al. (2007) identified mutations in the ATP1A2 gene in 5
(13%) of 39 patients with sporadic hemiplegic migraine. Three relatives
of 1 of these patients were subsequently found to carry the same ATP1A2
mutation: 1 developed FHM, and 2 remained asymptomatic, indicating
reduced penetrance.

PATHOGENESIS

Upon venous infusion of CGRP (114130), Hansen et al. (2008) found no
difference in the incidence of reported migraines or migraine-like
headaches between 10 controls and 9 patients with familial hemiplegic
migraine (FHM1 or FHM2). CGRP did not induce aura in any individuals.
The findings suggested that FHM patients do not show hypersensitivity to
the CGRP pathway, as had been observed in patients with migraine without
aura (MO), suggesting that the FHM and MO phenotypes have different
pathophysiologic mechanisms.

*FIELD* RF
1. Ambrosini, A.; D'Onofrio, M.; Grieco, G. S.; Di Mambro, A.; Montagna,
G.; Fortini, D.; Nicoletti, F.; Nappi, G.; Sances, G.; Schoenen, J.;
Buzzi, M. G.; Santorelli, F. M.; Pierelli, F.: Familial basilar migraine
associated with a new mutation in the ATP1A2 gene. Neurology 66:
1826-1828, 2005.

2. Castro, M.-J.; Nunes, B.; de Vries, B.; Lemos, C.; Vanmolkot, K.
R. J.; van den Heuvel, J. J. M. W.; Temudo, T.; Barros, J.; Sequeiros,
J.; Frants, R. R.; Koenderink, J. B.; Pereira-Monteiro, J. M.; van
den Maagdenberg, A. M. J. M.: Two novel functional mutations in the
Na+, K+-ATPase alpha-2-subunit ATP1A2 gene in patients with familial
hemiplegic migraine and associated neurological phenotypes. Clin.
Genet. 73: 37-43, 2008.

3. De Fusco, M.; Marconi, R.; Silvestri, L.; Atorino, L.; Rampoldi,
L.; Morgante, L.; Ballabio, A.; Aridon, P.; Casari, G.: Haploinsufficiency
of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with
familial hemiplegic migraine type 2. Nature Genet. 33: 192-196,
2003.

4. De Vries, B.; Freilinger, T.; Vanmolkot, K. R. J.; Koenderink,
J. B.; Stam, A. H.; Terwindt, G. M.; Babini, E.; van den Boogerd,
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R.; Kopp, U. A.; Lehmann-Horn, F.; Friedman, A.; Dichgans, M.: Opening
of the blood-brain barrier preceding cortical edema in a severe attack
of FHM type II. Neurology 64: 2145-2147, 2005.

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with a novel FHM2 ATP1A2 mutation. Ann. Neurol. 59: 310-314, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Hemianopic blurring of vision

NEUROLOGIC:
[Central nervous system];
Migraine;
Migraine with aura;
Hemiparesis;
Hemiplegia;
Hemihypoasthesia;
Seizures (less common);
Drowsiness;
Confusion;
Coma (less common);
Dysphasia;
Aphasia;
Unusual aura symptoms include alien limb phenomenon, diplopia, apraxia,
dysarthria, impaired hearing, vertigo;
Diffuse brain swelling occurs during coma;
Ictal EEG shows diffuse slow delta and theta activity;
Cerebellar signs during episodes;
Cerebellar ataxia during episodes;
Mental retardation (less common)

METABOLIC FEATURES:
Fever

MISCELLANEOUS:
Onset 6 to 30 years;
Highly variable frequency and duration of episodes;
Headaches last hours to days;
Neurologic signs last hours to days;
Episodes may be triggered by exercise, emotional stress, head trauma,
angiography, lack of sleep, heat;
Reduced penetrance (approximately 87%);
Genetic heterogeneity (see FHM1 141500 and MGR6 607516);
Alternating hemiplegia of childhood (104290) is an allelic disorder
with an overlapping phenotype

MOLECULAR BASIS:
Caused by mutation in the ATPase, Na+K+ transporting, alpha-2 polypeptide
gene (ATP1A2, 182340.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/9/2005
Cassandra L. Kniffin - updated: 10/25/2004

*FIELD* CD
Cassandra L. Kniffin: 1/27/2003

*FIELD* ED
joanna: 03/29/2005
ckniffin: 3/9/2005
ckniffin: 10/25/2004
joanna: 2/11/2003
ckniffin: 2/5/2003
ckniffin: 1/27/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 10/22/2010
Cassandra L. Kniffin - updated: 3/24/2009
Cassandra L. Kniffin - updated: 4/3/2008
Cassandra L. Kniffin - updated: 3/17/2008
Cassandra L. Kniffin - updated: 8/16/2007
Cassandra L. Kniffin - updated: 4/7/2006
Cassandra L. Kniffin - updated: 4/3/2006
Cassandra L. Kniffin - updated: 11/2/2005
Victor A. McKusick - updated: 9/1/2005
Cassandra L. Kniffin - updated: 3/9/2005
Cassandra L. Kniffin - updated: 10/25/2004
Cassandra L. Kniffin - updated: 12/30/2003
Cassandra L. Kniffin - updated: 5/7/2003
Victor A. McKusick - updated: 5/9/2002

*FIELD* CD
Victor A. McKusick: 3/27/1998

*FIELD* ED
carol: 09/14/2012
carol: 3/23/2012
wwang: 11/1/2010
ckniffin: 10/22/2010
alopez: 9/28/2010
terry: 9/27/2010
wwang: 3/31/2009
ckniffin: 3/24/2009
wwang: 4/15/2008
ckniffin: 4/3/2008
wwang: 3/18/2008
ckniffin: 3/17/2008
wwang: 8/24/2007
ckniffin: 8/16/2007
alopez: 4/12/2006
wwang: 4/11/2006
ckniffin: 4/7/2006
wwang: 4/5/2006
ckniffin: 4/3/2006
wwang: 11/23/2005
ckniffin: 11/14/2005
wwang: 11/11/2005
ckniffin: 11/2/2005
alopez: 9/9/2005
terry: 9/1/2005
wwang: 3/16/2005
ckniffin: 3/9/2005
tkritzer: 10/28/2004
ckniffin: 10/25/2004
ckniffin: 8/4/2004
tkritzer: 1/16/2004
ckniffin: 12/30/2003
tkritzer: 6/9/2003
ckniffin: 5/7/2003
carol: 2/3/2003
alopez: 1/31/2003
carol: 1/30/2003
ckniffin: 1/28/2003
ckniffin: 1/27/2003
cwells: 5/28/2002
cwells: 5/15/2002
terry: 5/9/2002
carol: 2/18/1999
alopez: 3/27/1998