RBCC Red Blood Cell Collection

ATP2B3 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Plasma membrane calcium-transporting ATPase 3; PMCA3; 3.6.3.8 (Plasma membrane calcium ATPase isoform 3; Plasma membrane calcium pump isoform 3)

UniProt Q16720
ID AT2B3_HUMAN Reviewed; 1220 AA.
AC Q16720; B7WNR8; B7WNY5; Q12995; Q16858;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 3.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Plasma membrane calcium-transporting ATPase 3;
DE Short=PMCA3;
DE EC=3.6.3.8;
DE AltName: Full=Plasma membrane calcium ATPase isoform 3;
DE AltName: Full=Plasma membrane calcium pump isoform 3;
GN Name=ATP2B3;
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 [MRNA] (ISOFORMS XA AND XB).
RC TISSUE=Brain;
RX PubMed=8765088; DOI=10.1016/0005-2736(96)00108-3;
RA Brown B., Hilfiker H., Demarco S.J., Zacharias D.A., Greenwood T.M.,
RA Carafoli E., Strehler E.E.;
RT "Primary structure of human plasma membrane Ca(2+)-ATPase isoform 3.";
RL Biochim. Biophys. Acta 1283:10-13(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-319, AND ALTERNATIVE SPLICING
RP (ISOFORMS XB/XA/XE/XG).
RX PubMed=8187550;
RA Wang M.G., Yi H., Hilfiker H., Carafoli E., Strehler E.E.,
RA McBride O.W.;
RT "Localization of two genes encoding plasma membrane Ca2+ ATPases
RT isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes 3p26-->p25 and
RT Xq28, respectively.";
RL Cytogenet. Cell Genet. 67:41-45(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-1053, AND ALTERNATIVE SPLICING
RP (ISOFORMS XB/XA/XE/XG).
RX PubMed=10854409; DOI=10.1101/gr.10.6.758;
RA Mallon A.-M., Platzer M., Bate R., Gloeckner G., Botcherby M.R.M.,
RA Nordsiek G., Strivens M.A., Kioschis P., Dangel A., Cunningham D.,
RA Straw R.N.A., Weston P., Gilbert M., Fernando S., Goodall K.,
RA Hunter G., Greystrong J.S., Clarke D., Kimberley C., Goerdes M.,
RA Blechschmidt K., Rump A., Hinzmann B., Mundy C.R., Miller W.,
RA Poustka A., Herman G.E., Rhodes M., Denny P., Rosenthal A.,
RA Brown S.D.M.;
RT "Comparative genome sequence analysis of the Bpa/Str region in mouse
RT and man.";
RL Genome Res. 10:758-775(2000).
RN [6]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS XG/ZG AND XA/ZA), AND
RP ALTERNATIVE SPLICING.
RC TISSUE=Brain cortex;
RX PubMed=8245032;
RA Stauffer T.P., Hilfiker H., Carafoli E., Strehler E.E.;
RT "Quantitative analysis of alternative splicing options of human plasma
RT membrane calcium pump genes.";
RL J. Biol. Chem. 268:25993-26003(1993).
RN [7]
RP ERRATUM.
RX PubMed=7989379;
RA Stauffer T.P., Hilfiker H., Carafoli E., Strehler E.E.;
RL J. Biol. Chem. 269:32022-32022(1994).
RN [8]
RP INTERACTION WITH PDZD11.
RX PubMed=12763866;
RA Goellner G.M., DeMarco S.J., Strehler E.E.;
RT "Characterization of PISP, a novel single-PDZ protein that binds to
RT all plasma membrane Ca2+-ATPase b-splice variants.";
RL Ann. N. Y. Acad. Sci. 986:461-471(2003).
RN [9]
RP TISSUE SPECIFICITY, VARIANT SCAX1 ASP-1107, AND CHARACTERIZATION OF
RP VARIANT SCAX1 ASP-1107.
RX PubMed=22912398; DOI=10.1073/pnas.1207488109;
RA Zanni G., Cali T., Kalscheuer V.M., Ottolini D., Barresi S.,
RA Lebrun N., Montecchi-Palazzi L., Hu H., Chelly J., Bertini E.,
RA Brini M., Carafoli E.;
RT "Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-
RT linked congenital cerebellar ataxia impairs Ca2+ homeostasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:14514-14519(2012).
CC -!- FUNCTION: This magnesium-dependent enzyme catalyzes the hydrolysis
CC of ATP coupled with the transport of calcium out of the cell.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O + Ca(2+)(Side 1) = ADP + phosphate
CC + Ca(2+)(Side 2).
CC -!- SUBUNIT: Interacts with PDZD11.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Comment=There is a combination of two alternatively spliced
CC domains at N-terminal site A (X and Z) and at C-terminal site C
CC (A, B, E and G). The splice sites have mostly been studied
CC independently. Full isoforms so far detected are isoform XA and
CC isoform XB. Experimental confirmation may be lacking for some
CC isoforms;
CC Name=XB; Synonyms=AIICI;
CC IsoId=Q16720-1; Sequence=Displayed;
CC Name=XA; Synonyms=AIICII;
CC IsoId=Q16720-2; Sequence=VSP_000393;
CC Name=ZA; Synonyms=AICII;
CC IsoId=Q16720-3; Sequence=VSP_000392, VSP_000393;
CC Name=ZB; Synonyms=AICI;
CC IsoId=Q16720-4; Sequence=VSP_000392;
CC Name=XE; Synonyms=AIICV;
CC IsoId=Q16720-5; Sequence=VSP_000394;
CC Name=ZE; Synonyms=AICV;
CC IsoId=Q16720-6; Sequence=VSP_000392, VSP_000394;
CC Name=XG; Synonyms=AIICVII;
CC IsoId=Q16720-7; Sequence=VSP_000395;
CC Name=ZG; Synonyms=AICVII;
CC IsoId=Q16720-8; Sequence=VSP_000392, VSP_000395;
CC -!- TISSUE SPECIFICITY: Highly expressed in the cerebellum,
CC particulary in the presynaptic terminals of parallel fibers-
CC Purkinje neurons. Isoform XE and isoform XB are the most abundant
CC isoforms and are detected at low levels in brain and fetal
CC skeletal muscle. The other isoforms are only found at lower levels
CC and not in fetal tissues.
CC -!- DISEASE: Spinocerebellar ataxia, X-linked 1 (SCAX1) [MIM:302500]:
CC Spinocerebellar ataxia is a clinically and genetically
CC heterogeneous group of cerebellar disorders. Patients show
CC progressive incoordination of gait and often poor coordination of
CC hands, speech and eye movements, due to degeneration of the
CC cerebellum with variable involvement of the brainstem and spinal
CC cord. SCAX1 is characterized by hypotonia at birth, delayed motor
CC development, gait ataxia, difficulty standing, dysarthria, and
CC slow eye movements. Brain MRI shows cerebellar ataxia. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the cation transport ATPase (P-type)
CC (TC 3.A.3) family. Type IIB subfamily.
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DR EMBL; U57971; AAB09762.1; -; mRNA.
DR EMBL; U60414; AAB38530.1; -; mRNA.
DR EMBL; AH006061; AAC15078.1; -; Genomic_DNA.
DR EMBL; CH471172; EAW72859.1; -; Genomic_DNA.
DR EMBL; U82695; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U15689; AAA60986.1; -; mRNA.
DR EMBL; U15690; AAA60987.1; -; mRNA.
DR RefSeq; NP_001001344.1; NM_001001344.2.
DR RefSeq; NP_068768.2; NM_021949.3.
DR RefSeq; XP_005274747.1; XM_005274690.1.
DR RefSeq; XP_005274748.1; XM_005274691.1.
DR RefSeq; XP_005274749.1; XM_005274692.1.
DR RefSeq; XP_005274750.1; XM_005274693.1.
DR RefSeq; XP_005277914.1; XM_005277857.1.
DR RefSeq; XP_005277915.1; XM_005277858.1.
DR RefSeq; XP_005277916.1; XM_005277859.1.
DR RefSeq; XP_005277917.1; XM_005277860.1.
DR UniGene; Hs.533956; -.
DR UniGene; Hs.658008; -.
DR ProteinModelPortal; Q16720; -.
DR SMR; Q16720; 66-943, 1097-1124.
DR IntAct; Q16720; 1.
DR MINT; MINT-2807671; -.
DR STRING; 9606.ENSP00000263519; -.
DR PhosphoSite; Q16720; -.
DR DMDM; 116241261; -.
DR PaxDb; Q16720; -.
DR PRIDE; Q16720; -.
DR Ensembl; ENST00000263519; ENSP00000263519; ENSG00000067842.
DR Ensembl; ENST00000349466; ENSP00000343886; ENSG00000067842.
DR Ensembl; ENST00000359149; ENSP00000352062; ENSG00000067842.
DR Ensembl; ENST00000370181; ENSP00000359200; ENSG00000067842.
DR Ensembl; ENST00000370186; ENSP00000359205; ENSG00000067842.
DR Ensembl; ENST00000393842; ENSP00000377425; ENSG00000067842.
DR Ensembl; ENST00000571862; ENSP00000460932; ENSG00000263148.
DR Ensembl; ENST00000571969; ENSP00000461370; ENSG00000263148.
DR Ensembl; ENST00000572057; ENSP00000458650; ENSG00000263148.
DR Ensembl; ENST00000575463; ENSP00000460886; ENSG00000263148.
DR Ensembl; ENST00000601388; ENSP00000471537; ENSG00000263148.
DR Ensembl; ENST00000602058; ENSP00000468854; ENSG00000263148.
DR GeneID; 492; -.
DR KEGG; hsa:492; -.
DR UCSC; uc004fht.1; human.
DR CTD; 492; -.
DR GeneCards; GC0XP152783; -.
DR H-InvDB; HIX0017131; -.
DR HGNC; HGNC:816; ATP2B3.
DR HPA; CAB005607; -.
DR HPA; HPA001583; -.
DR MIM; 300014; gene.
DR MIM; 302500; phenotype.
DR neXtProt; NX_Q16720; -.
DR Orphanet; 314978; X-linked non progressive cerebellar ataxia.
DR PharmGKB; PA25109; -.
DR eggNOG; COG0474; -.
DR HOGENOM; HOG000265623; -.
DR HOVERGEN; HBG061286; -.
DR InParanoid; Q16720; -.
DR KO; K05850; -.
DR OMA; HGTKSAT; -.
DR OrthoDB; EOG7SN8BN; -.
DR PhylomeDB; Q16720; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR GeneWiki; ATP2B3; -.
DR GenomeRNAi; 492; -.
DR NextBio; 2065; -.
DR PRO; PR:Q16720; -.
DR ArrayExpress; Q16720; -.
DR Bgee; Q16720; -.
DR CleanEx; HS_ATP2B3; -.
DR Genevestigator; Q16720; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005388; F:calcium-transporting ATPase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR Gene3D; 1.20.1110.10; -; 3.
DR InterPro; IPR022141; ATP_Ca_trans_C.
DR InterPro; IPR006408; ATPase_P-typ_Ca-transp_plasma.
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; 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; PF12424; ATP_Ca_trans_C; 1.
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; TIGR01517; ATPase-IIB_Ca; 1.
DR TIGRFAMs; TIGR01494; ATPase_P-type; 3.
DR PROSITE; PS00154; ATPASE_E1_E2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Calcium; Calcium transport;
KW Calmodulin-binding; Cell membrane; Complete proteome;
KW Disease mutation; Hydrolase; Ion transport; Magnesium; Membrane;
KW Metal-binding; Neurodegeneration; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1 1220 Plasma membrane calcium-transporting
FT ATPase 3.
FT /FTId=PRO_0000046218.
FT TOPO_DOM 1 97 Cytoplasmic (Potential).
FT TRANSMEM 98 118 Helical; (Potential).
FT TOPO_DOM 119 155 Extracellular (Potential).
FT TRANSMEM 156 176 Helical; (Potential).
FT TOPO_DOM 177 364 Cytoplasmic (Potential).
FT TRANSMEM 365 384 Helical; (Potential).
FT TOPO_DOM 385 417 Extracellular (Potential).
FT TRANSMEM 418 435 Helical; (Potential).
FT TOPO_DOM 436 849 Cytoplasmic (Potential).
FT TRANSMEM 850 869 Helical; (Potential).
FT TOPO_DOM 870 879 Extracellular (Potential).
FT TRANSMEM 880 900 Helical; (Potential).
FT TOPO_DOM 901 920 Cytoplasmic (Potential).
FT TRANSMEM 921 943 Helical; (Potential).
FT TOPO_DOM 944 961 Extracellular (Potential).
FT TRANSMEM 962 983 Helical; (Potential).
FT TOPO_DOM 984 1002 Cytoplasmic (Potential).
FT TRANSMEM 1003 1024 Helical; (Potential).
FT TOPO_DOM 1025 1034 Extracellular (Potential).
FT TRANSMEM 1035 1056 Helical; (Potential).
FT TOPO_DOM 1057 1220 Cytoplasmic (Potential).
FT REGION 1097 1114 Calmodulin-binding subdomain A (By
FT similarity).
FT REGION 1115 1124 Calmodulin-binding subdomain B (By
FT similarity).
FT COMPBIAS 297 300 Poly-Glu.
FT COMPBIAS 1174 1179 Poly-Pro.
FT ACT_SITE 473 473 4-aspartylphosphate intermediate (By
FT similarity).
FT METAL 794 794 Magnesium (By similarity).
FT METAL 798 798 Magnesium (By similarity).
FT MOD_RES 1113 1113 Phosphothreonine; by PKC (By similarity).
FT VAR_SEQ 306 319 Missing (in isoform ZA, isoform ZB,
FT isoform ZE and isoform ZG).
FT /FTId=VSP_000392.
FT VAR_SEQ 1115 1220 IRVVKAFRSSLYEGLEKPESKTSIHNFMATPEFLINDYTHN
FT IPLIDDTDVDENEERLRAPPPPSPNQNNNAIDSGIYLTTHV
FT TKSATSSVFSSSPGSPLHSVETSL -> MEVVSTFKRSGSV
FT QGAVRRRSSVLSQLHDVTNLSTPTHAILSAANPTSAAGNPG
FT GESVP (in isoform XA and isoform ZA).
FT /FTId=VSP_000393.
FT VAR_SEQ 1115 1220 IRVVKAFRSSLYEGLEKPESKTSIHNFMATPEFLINDYTHN
FT IPLIDDTDVDENEERLRAPPPPSPNQNNNAIDSGIYLTTHV
FT TKSATSSVFSSSPGSPLHSVETSL -> MEVVSTFKRSGSV
FT QGAVRRRSSVLSQLHDVTNLSTPTHAILSAANPTSAAGSES
FT (in isoform XE and isoform ZE).
FT /FTId=VSP_000394.
FT VAR_SEQ 1115 1220 IRVVKAFRSSLYEGLEKPESKTSIHNFMATPEFLINDYTHN
FT IPLIDDTDVDENEERLRAPPPPSPNQNNNAIDSGIYLTTHV
FT TKSATSSVFSSSPGSPLHSVETSL -> VCWDGKKMLRTTE
FT VG (in isoform XG and isoform ZG).
FT /FTId=VSP_000395.
FT VARIANT 198 198 I -> M (in dbSNP:rs2269409).
FT /FTId=VAR_027928.
FT VARIANT 1107 1107 G -> D (in SCAX1; the mutant protein is
FT expressed at the plasma membrane but
FT shows impaired extrusion of intracellular
FT calcium with prolonged retention of
FT cytoplasmic calcium compared to wild-type
FT under physiologic conditions).
FT /FTId=VAR_069308.
FT CONFLICT 587 587 I -> V (in Ref. 1; AAB09762/AAB38530).
FT CONFLICT 654 654 S -> Y (in Ref. 1; AAB09762/AAB38530).
SQ SEQUENCE 1220 AA; 134197 MW; 03B2BA8A0A33B193 CRC64;
MGDMANSSIE FHPKPQQQRD VPQAGGFGCT LAELRTLMEL RGAEALQKIE EAYGDVSGLC
RRLKTSPTEG LADNTNDLEK RRQIYGQNFI PPKQPKTFLQ LVWEALQDVT LIILEVAAIV
SLGLSFYAPP GEESEACGNV SGGAEDEGEA EAGWIEGAAI LLSVICVVLV TAFNDWSKEK
QFRGLQSRIE QEQKFTVIRN GQLLQVPVAA LVVGDIAQVK YGDLLPADGV LIQANDLKID
ESSLTGESDH VRKSADKDPM LLSGTHVMEG SGRMVVTAVG VNSQTGIIFT LLGAGGEEEE
KKDKKGKQQD GAMESSQTKA KKQDGAVAME MQPLKSAEGG EMEEREKKKA NAPKKEKSVL
QGKLTKLAVQ IGKAGLVMSA ITVIILVLYF VIETFVVEGR TWLAECTPVY VQYFVKFFII
GVTVLVVAVP EGLPLAVTIS LAYSVKKMMK DNNLVRHLDA CETMGNATAI CSDKTGTLTT
NRMTVVQSYL GDTHYKEIPA PSALTPKILD LLVHAISINS AYTTKILPPE KEGALPRQVG
NKTECALLGF VLDLKRDFQP VREQIPEDKL YKVYTFNSVR KSMSTVIRMP DGGFRLFSKG
ASEILLKKCT NILNSNGELR GFRPRDRDDM VRKIIEPMAC DGLRTICIAY RDFSAGQEPD
WDNENEVVGD LTCIAVVGIE DPVRPEVPEA IRKCQRAGIT VRMVTGDNIN TARAIAAKCG
IIQPGEDFLC LEGKEFNRRI RNEKGEIEQE RLDKVWPKLR VLARSSPTDK HTLVKGIIDS
TTGEQRQVVA VTGDGTNDGP ALKKADVGFA MGIAGTDVAK EASDIILTDD NFTSIVKAVM
WGRNVYDSIS KFLQFQLTVN VVAVIVAFTG ACITQDSPLK AVQMLWVNLI MDTFASLALA
TEPPTESLLL RKPYGRDKPL ISRTMMKNIL GHAVYQLAII FTLLFVGELF FDIDSGRNAP
LHSPPSEHYT IIFNTFVMMQ LFNEINARKI HGERNVFDGI FSNPIFCTIV LGTFGIQIVI
VQFGGKPFSC SPLSTEQWLW CLFVGVGELV WGQVIATIPT SQLKCLKEAG HGPGKDEMTD
EELAEGEEEI DHAERELRRG QILWFRGLNR IQTQIRVVKA FRSSLYEGLE KPESKTSIHN
FMATPEFLIN DYTHNIPLID DTDVDENEER LRAPPPPSPN QNNNAIDSGI YLTTHVTKSA
TSSVFSSSPG SPLHSVETSL
//
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MIM 300014
*RECORD*
*FIELD* NO
300014
*FIELD* TI
*300014 ATPase, Ca(2+)-TRANSPORTING, PLASMA MEMBRANE, 3; ATP2B3
;;PLASMA MEMBRANE Ca(2+)-ATPase, TYPE 3; PMCA3
read more*FIELD* TX

DESCRIPTION

The ATP2B3 gene encodes a calcium-transporting ATPase predominantly
expressed in the brain (summary by Brown et al., 1996). The
Ca(2+)-ATPases are a family of plasma membrane pumps encoded by at least
4 genes: ATP2B1 (108731) on chromosome 12q21; ATP2B2 (108733) on 3p26;
ATP2B3; and ATP2B4 (108732) on 1q25.

CLONING

Stahl et al. (1992) showed that the products of the rat ATP2B2 and
ATP2B3 genes are particularly abundant in some brain regions.

By PCR, Brandt et al. (1992) detected human PMCA3 expression in spinal
cord and brain. A splice variant, PMCA3b, was expressed in adrenal
gland, spinal cord, and brain. The presence of 3 other PCR products,
primarily in spinal cord, suggested the presence of additional
alternatively spliced variants.

Brown et al. (1996) isolated 2 main isoforms for the ATP2B3 cDNA,
designated 3a and 3b, which encode 1,173- and 1,220-amino acid proteins,
respectively. Northern blot analysis detected a 7-kb mRNA transcript
exclusively in the brain.

Zanni et al. (2012) found high expression of the full-length ATP2B3
isoform in presynaptic terminals of parallel fibers-Purkinje neurons in
the cerebellum.

MAPPING

By fluorescence in situ hybridization, analysis of somatic cell hybrids,
and genetic linkage analysis of CEPH families, Wang et al. (1994) mapped
the ATP2B3 gene to chromosome Xq28.

MOLECULAR GENETICS

In affected members of the family with early-onset X-linked
spinocerebellar ataxia-1 (SCAX1; 302500) originally reported by Bertini
et al. (2000), Zanni et al. (2012) identified a mutation in the ATP2B3
(G1107D; 300014.0001). The mutation was identified by X-exome sequencing
and confirmed by Sanger sequencing. In vitro functional expression
studies showed that the mutant protein had defective intracellular
calcium clearance compared to wildtype, suggesting that the disorder
resulted from defective calcium homeostasis in neurons.

- Somatic Mutation

Beuschlein et al. (2013) performed exome sequencing of
aldosterone-producing adenomas and identified somatic hotspot mutations
in the ATP1A1 (182310) gene, encoding a sodium/potassium ATPase alpha
subunit, and the ATP2B3 gene, encoding a calcium ATPase, in 3 and 2 of
the 9 aldosterone-producing adenomas, respectively. These ATPases are
expressed in adrenal cells and control sodium, potassium, and calcium
ion homeostasis. Functional in vitro studies of the ATP1A1 mutants
showed loss of pump activity and strongly reduced affinity for
potassium. Electrophysiologic ex vivo studies on primary adrenal adenoma
cells provided further evidence for inappropriate depolarization of
cells with ATPase alterations. In a collection of 308
aldosterone-producing adenomas, Beuschlein et al. (2013) found 16 (5.2%)
somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive
cases showed male dominance, increased plasma aldosterone
concentrations, and lower potassium concentrations compared with
mutation-negative cases.

*FIELD* AV
.0001
SPINOCEREBELLAR ATAXIA, X-LINKED 1 (1 family)
ATP2B3, GLY1107ASP

In a boy and his uncle with X-linked spinocerebellar ataxia-1 (SCAX1;
302500) originally reported by Bertini et al. (2000), Zanni et al.
(2012) identified a 3321G-A transition in exon 20 of the ATP2B3 gene,
resulting in a gly1107-to-asp (G1107D) substitution at a highly
conserved residue in the calmodulin-binding domain. The mutation was
identified by X-exome sequencing and confirmed by Sanger sequencing.
Construction of the mutant protein by site-directed mutagenesis and
expression of the mutation in HeLa cells showed that the mutant protein
was expressed at the plasma membrane, but showed impaired extrusion of
intracellular calcium with prolonged retention of cytoplasmic calcium
compared to wildtype under physiologic conditions. Detailed analysis of
the mutant protein in response to intracellular calcium increase from
intracellular stores compared to extracellular influx showed subtle
differences in mutant pump response, but was consistent with decreased
calcium clearance from the cell. The findings indicated the importance
of calcium homeostasis in neurons.

*FIELD* RF
1. Bertini, E.; des Portes, V.; Zanni, G.; Santorelli, F.; Dionisi-Vici,
C.; Vicari, S.; Fariello, G.; Chelly, J.: X-linked congenital ataxia:
a clinical and genetic study. Am. J. Med. Genet. 92: 53-56, 2000.

2. Beuschlein, F.; Boulkroun, S.; Osswald, A.; Wieland, T.; Nielsen,
H. N.; Lichtenauer, U. D.; Penton, D.; Schack, V. R.; Amar, L.; Fischer,
E.; Walther, A.; Tauber, P.; and 18 others: Somatic mutations in
ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary
hypertension. Nature Genet 45: 440-444, 2013.

3. Brandt, P.; Neve, R. L.; Kammesheidt, A.; Rhoads, R. E.; Vanaman,
T. C.: Analysis of the tissue-specific distribution of mRNAs encoding
the plasma membrane calcium-pumping ATPases and characterization of
an alternately spliced form of PMCA4 at the cDNA and genomic levels. J.
Biol. Chem. 267: 4376-4385, 1992.

4. Brown, B. J.; Hilfiker, H.; DeMarco, S. J.; Zacharias, D. A.; Greenwood,
T. M.; Guerini, D.; Strehler, E. E.: Primary structure of human plasma
membrane Ca(2+)-ATPase isoform 3. Biochim. Biophys. Acta 1283: 10-13,
1996.

5. Stahl, W. L.; Eakin, T. J.; Owens, J. W. M., Jr.; Breininger, J.
F.; Filuk, P. E.; Anderson, W. R.: Plasma membrane Ca(2+)-ATPase
isoforms: distribution of mRNAs in rat brain by in situ hybridization. Molec.
Brain Res. 16: 223-231, 1992.

6. Wang, M. G.; Yi, H.; Hilfiker, H.; Carafoli, E.; Strehler, E. E.;
McBride, O. W.: Localization of two genes encoding plasma membrane
Ca(2+)-ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes
3p26-p25 and Xq28, respectively. Cytogenet. Cell Genet. 67: 41-45,
1994.

7. Zanni, G.; Cali, T.; Kalscheuer, V. M.; Ottolini, D.; Barresi,
S.; Lebrun, N.; Montecchi-Palazzi, L.; Hu, H.; Chelly, J.; Bertini,
E.; Brini, M.; Carafoli, E.: Mutation of plasma membrane Ca(2+) ATPase
isoform 3 in a family with X-linked congenital cerebellar ataxia impairs
Ca(2+) homeostasis. Proc. Nat. Acad. Sci. 109: 14514-14519, 2012.

*FIELD* CN
Ada Hamosh - updated: 10/23/2013
Cassandra L. Kniffin - updated: 12/4/2012
Patricia A. Hartz - updated: 2/8/2005
Cassandra L. Kniffin - updated: 11/22/2004

*FIELD* CD
Victor A. McKusick: 2/4/1996

*FIELD* ED
carol: 02/12/2014
carol: 10/25/2013
alopez: 10/23/2013
carol: 12/5/2012
ckniffin: 12/4/2012
mgross: 2/8/2005
tkritzer: 11/29/2004
ckniffin: 11/22/2004
joanna: 2/4/1996

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MIM 302500
*RECORD*
*FIELD* NO
302500
*FIELD* TI
#302500 SPINOCEREBELLAR ATAXIA, X-LINKED 1; SCAX1
;;OLIVOPONTOCEREBELLAR ATROPHY, X-LINKED;;
read moreOPCA, X-LINKED; OPCAX
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked spinocerebellar ataxia-1 (SCAX1) is caused by mutation in the
ATP2B3 gene (300014) on chromosome Xq28. One such family has been
reported.

DESCRIPTION

SCAX1 is an X-linked recessive neurologic disorder characterized by
hypotonia at birth, delayed motor development, gait ataxia, difficulty
standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar
ataxia (summary by Bertini et al., 2000).

- Genetic Heterogeneity of X-linked Spinocerebellar Ataxia

X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and
genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3
(301790), SCAX4 (301840), and SCAX5 (300703).

CLINICAL FEATURES

Shokeir (1970) described 3 kindreds in which a total of 16 affected
individuals had cerebellar ataxia transmitted in an X-linked recessive
pattern of inheritance. In 1 family, onset of lower limb weakness,
unsteady gait, and incoordination occurred between 16 and 20 years of
age, followed by dysarthria and nystagmus. The disorder was rapidly
progressive until about age 30 years and later became stable. The
proband, a 62-year-old man, also had lower limb spasticity with extensor
plantar responses. There were no skeletal deformities or sensory
deficits. Affected males in the second family were born of a
father-daughter union, although a maternal uncle and great-uncle were
reportedly affected. The proband in this family had onset at age 18 of
progressive incoordination, dysarthria, dysmetria, nystagmus, tremor,
and mild spasticity. The third family had a similar onset and disease
course; 1 of the affected persons in this family was a female with the
XO Turner syndrome, consistent with X-linked recessive inheritance. The
disease did not seem to affect life span, and intelligence was
unimpaired.

The propositus of the family studied by Bertini et al. (2000) was first
evaluated at age 1 year for delayed motor development. Hypotonia, mild
dysphagia, and delayed motor development were noted from birth. At the
age of 4 years, he showed action tremor of the upper limbs and slow eye
movements, but no pyramidal signs. Brain MRI at age 2 years was normal,
but at age 3 years showed global atrophy of the cerebellum. A maternal
uncle had had a similar course since birth and had been similarly
delayed in achieving psychomotor skills. When examined at age 36 years,
he showed moderate dysarthria, unsteady gait with truncal and locomotor
ataxia, intention tremor, and limitation of vertical gaze with slow
conjugate eye movements. Brain MRI showed severe global atrophy of the
cerebellar vermis and hemispheres.

MAPPING

Illarioshkin et al. (1996) mapped a locus for X-linked recessive
congenital ataxia in a Russian family to a large genetic interval (54
cM) on Xp11.21-q24. In an Italian family with clinical features very
similar to those in the Russian pedigree, Bertini et al. (2000)
performed a linkage study that narrowed the interval by 24 cM. Exclusion
of the interval between DXS990 and DXS424 left 2 critical regions: one
of 10 cM at Xq23-q24 and a second of 20 cM at Xp11.21-q21.3.

HETEROGENEITY

- Clinical Heterogeneity

Young et al. (1987) reported a family in which 3 boys, 2 full brothers
and a half brother, presented with marked delay in motor milestones,
severe limb and truncal ataxia, nystagmus, speech delay and moderate
global retardation. Inheritance was most consistent with X-linked
recessive.

Lutz et al. (1989) described apparent X-linked inheritance of a
relatively pure cerebellar degeneration. Clinical features included
infantile onset, cerebellar ataxia, very slow progression, mental
retardation, and cerebellar degeneration with involvement of the olive
and pons demonstrated by neuroimaging techniques.

In describing a Turkish family with ataxia combined with spastic
diplegia in 7 males, Apak et al. (1989) pointed out the confusing state
of the nosology of X-linked (spino)cerebellar ataxia/spastic paraplegia.
The family they reported showed onset of nystagmus in infancy, with
ataxia and pyramidal signs noted at age 2 to 3 years. The patients were
never able to walk. Dysarthria, orthopedic impairment, and mild mental
retardation appeared later as the disorder progressed. Death occurred in
the third or fourth decade from infections. The features did not agree
completely with any previously reported X-linked disorders.

MOLECULAR GENETICS

In the boy and his uncle with X-linked spinocerebellar ataxia-1
originally reported by Bertini et al. (2000), Zanni et al. (2012)
identified a mutation in the ATP2B3 gene (G1107D; 300014.0001). The
mutation was identified by X-exome sequencing and confirmed by Sanger
sequencing. In vitro functional expression studies showed that the
mutant protein had decreased extrusion of intracellular calcium compared
to wildtype, suggesting that the disorder resulted from defective
calcium homeostasis in neurons.

HISTORY

A kindred with X-linked inheritance of what the authors thought was
probably 'Friedreich ataxia' was reported by Turner and Roberts (1938).
Onset was at about 5 years of age and the victim was bedfast by about 20
years. The first carrier female in the kindred was of English
extraction. Brandenberg (1910) described 4 males with 'Friedreich
ataxia' in 3 generations of a family, related through females in a
pattern consistent with X-linkage.

*FIELD* SA
Malamud and Cohen (1958); Van Bogaert and Moreau (1939)
*FIELD* RF
1. Apak, S.; Yuksel, M.; Ozmen, M.; Saka, N.; Darendeliler, F.; Neuhauser,
G.: Heterogeneity of X-linked recessive (spino)cerebellar ataxia
with or without spastic diplegia. (Abstract) Am. J. Med. Genet. 34:
155-158, 1989.

2. Bertini, E.; des Portes, V.; Zanni, G.; Santorelli, F.; Dionisi-Vici,
C.; Vicari, S.; Fariello, G.; Chelly, J.: X-linked congenital ataxia:
a clinical and genetic study. Am. J. Med. Genet. 92: 53-56, 2000.

3. Brandenberg, F.: Kasuistische Beitrage zur gleichgeschlechtlichen
Vererbung. Arch. Rass. Ges. Biol. 7: 290-305, 1910.

4. Illarioshkin, S. N.; Tanaka, H.; Markova, E. D.; Nikolskaya, N.
N.; Ivanova-Smolenskaya, I. A.; Tsuji, S.: X-linked nonprogressive
congenital cerebellar hypoplasia: clinical description and mapping
to chromosome Xq. Ann. Neurol. 40: 75-83, 1996.

5. Lutz, R.; Bodensteiner, J.; Schaefer, B.; Gay, C.: X-linked olivopontocerebellar
atrophy. Clin. Genet. 35: 417-422, 1989.

6. Malamud, N.; Cohen, P.: Unusual form of cerebellar ataxia with
sex-linked inheritance. Neurology 8: 261-266, 1958.

7. Shokeir, M. H. K.: X-linked cerebellar ataxia. Clin. Genet. 1:
225-231, 1970.

8. Turner, E. V.; Roberts, E.: A family with a sex-linked hereditary
ataxia. J. Nerv. Ment. Dis. 87: 74-80, 1938.

9. Van Bogaert, L.; Moreau, M.: Combinaison de l'amyotrophie de Charcot-Marie-Tooth
et de la maladie de Friedreich chez plusieurs membres d'une meme famille. Encephale 34:
312-320, 1939.

10. Young, I. D.; Moore, J. R.; Tripp, J. H.: Sex-linked recessive
congenital ataxia. J. Neurol. Neurosurg. Psychiat. 50: 1230-1232,
1987.

11. Zanni, G.; Cali, T.; Kalscheuer, V. M.; Ottolini, D.; Barresi,
S.; Lebrun, N.; Montecchi-Palazzi, L.; Hu, H.; Chelly, J.; Bertini,
E.; Brini, M.; Carafoli, E.: Mutation of plasma membrane Ca(2+) ATPase
isoform 3 in a family with X-linked congenital cerebellar ataxia impairs
Ca(2+) homeostasis. Proc. Nat. Acad. Sci. 109: 14514-14519, 2012.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Eyes];
Strabismus;
Slow eye movements

MUSCLE, SOFT TISSUE:
Hypotonia, neonatal

NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Cerebellar ataxia;
Dysarthria;
Difficulty standing independently;
Action tremor;
Intention tremor;
Cerebellar atrophy

MISCELLANEOUS:
Onset at birth;
Nonprogressive disorder;
One family with a confirmed pathogenic ATP2B3 mutation has been reported
(last curated December 2012)

MOLECULAR BASIS:
Caused by mutation in the plasma membrane Ca(2+)-transporting ATPase
3 gene (ATP2B3, 300014.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 12/4/2012

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/17/2013
ckniffin: 12/4/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2012
Cassandra L. Kniffin - updated: 4/16/2008
Cassandra L. Kniffin - updated: 7/6/2006
Cassandra L. Kniffin - updated: 5/2/2006
Victor A. McKusick - updated: 4/25/2000

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 02/12/2014
ckniffin: 2/10/2014
carol: 12/5/2012
ckniffin: 12/4/2012
wwang: 4/17/2008
ckniffin: 4/16/2008
ckniffin: 7/6/2006
wwang: 5/4/2006
ckniffin: 5/2/2006
ckniffin: 10/18/2005
alopez: 3/17/2004
mcapotos: 5/24/2000
mcapotos: 5/23/2000
terry: 4/25/2000
carol: 8/13/1999
terry: 7/25/1994
mimadm: 2/27/1994
supermim: 3/17/1992
carol: 12/10/1990
supermim: 3/20/1990
carol: 11/14/1989

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