Full text data of ANK2
ANK2
[Confidence: low (only semi-automatic identification from reviews)]
Ankyrin-2; ANK-2 (Ankyrin-B; Brain ankyrin; Non-erythroid ankyrin)
Ankyrin-2; ANK-2 (Ankyrin-B; Brain ankyrin; Non-erythroid ankyrin)
UniProt
Q01484
ID ANK2_HUMAN Reviewed; 3957 AA.
AC Q01484; Q01485; Q08AC7; Q08AC8; Q7Z3L5;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-MAY-2012, sequence version 4.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Ankyrin-2;
DE Short=ANK-2;
DE AltName: Full=Ankyrin-B;
DE AltName: Full=Brain ankyrin;
DE AltName: Full=Non-erythroid ankyrin;
GN Name=ANK2;
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] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 1477-2110 (ISOFORM 3), AND TISSUE SPECIFICITY.
RC TISSUE=Brain stem;
RX PubMed=1830053; DOI=10.1083/jcb.114.2.241;
RA Otto E., Kunimoto M., McLaughlin T., Bennett V.;
RT "Isolation and characterization of cDNAs encoding human brain ankyrins
RT reveal a family of alternatively spliced genes.";
RL J. Cell Biol. 114:241-253(1991).
RN [2]
RP SEQUENCE REVISION.
RA Carpenter S.;
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Brain stem;
RX PubMed=8253844; DOI=10.1083/jcb.123.6.1463;
RA Chan W., Kordeli E., Bennett V.;
RT "440-kD ankyrinB: structure of the major developmentally regulated
RT domain and selective localization in unmyelinated axons.";
RL J. Cell Biol. 123:1463-1473(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 463-495, AND TISSUE SPECIFICITY.
RX PubMed=1833308; DOI=10.1016/0888-7543(91)90173-C;
RA Tse W.T., Menninger J.C., Yang-Feng T.L., Francke U., Sahr K.E.,
RA Lux S.E., Ward D.C., Forget B.G.;
RT "Isolation and chromosomal localization of a novel nonerythroid
RT ankyrin gene.";
RL Genomics 10:858-866(1991).
RN [8]
RP FUNCTION, AND VARIANT LQT4 GLY-1458.
RX PubMed=12571597; DOI=10.1038/nature01335;
RA Mohler P.J., Schott J.-J., Gramolini A.O., Dilly K.W., Guatimosim S.,
RA duBell W.H., Song L.-S., Haurogne K., Kyndt F., Ali M.E., Rogers T.B.,
RA Lederer W.J., Escande D., Le Marec H., Bennett V.;
RT "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
RT sudden cardiac death.";
RL Nature 421:634-639(2003).
RN [9]
RP INTERACTION WITH SPTBN1, AND MUTAGENESIS OF 975-ASP--ARG-977; ALA-1000
RP AND 1100-GLU--ASP-1103.
RX PubMed=15262991; DOI=10.1074/jbc.M406018200;
RA Mohler P.J., Yoon W., Bennett V.;
RT "Ankyrin-B targets beta2-spectrin to an intracellular compartment in
RT neonatal cardiomyocytes.";
RL J. Biol. Chem. 279:40185-40193(2004).
RN [10]
RP INTERACTION WITH RHBG.
RX PubMed=15611082; DOI=10.1074/jbc.M413351200;
RA Lopez C., Metral S., Eladari D., Drevensek S., Gane P., Chambrey R.,
RA Bennett V., Cartron J.-P., Le Van Kim C., Colin Y.;
RT "The ammonium transporter RhBG: requirement of a tyrosine-based signal
RT and ankyrin-G for basolateral targeting and membrane anchorage in
RT polarized kidney epithelial cells.";
RL J. Biol. Chem. 280:8221-8228(2005).
RN [11]
RP SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=19007774; DOI=10.1016/j.exer.2008.09.022;
RA Kizhatil K., Sandhu N.K., Peachey N.S., Bennett V.;
RT "Ankyrin-B is required for coordinated expression of beta-2-spectrin,
RT the Na/K-ATPase and the Na/Ca exchanger in the inner segment of rod
RT photoreceptors.";
RL Exp. Eye Res. 88:57-64(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 966-3620, DOMAIN DEATH 1,
RP DOMAIN UPA, AND DOMAINS ZU5.
RX PubMed=22411828; DOI=10.1073/pnas.1200613109;
RA Wang C., Yu C., Ye F., Wei Z., Zhang M.;
RT "Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals
RT interaction surfaces necessary for ankyrin function.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:4822-4827(2012).
RN [15]
RP VARIANTS LQT4 GLY-1458; ILE-3740; ASN-3744; TRP-3906 AND LYS-3931, AND
RP CHARACTERIZATION OF VARIANTS LQT4.
RX PubMed=15178757; DOI=10.1073/pnas.0402546101;
RA Mohler P.J., Splawski I., Napolitano C., Bottelli G., Sharpe L.,
RA Timothy K., Priori S.G., Keating M.T., Bennett V.;
RT "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:9137-9142(2004).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] GLU-685; ARG-1267 AND LYS-3653.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: In skeletal muscle, required for proper localization of
CC DMD and DCTN4 and for the formation and/or stability of a special
CC subset of microtubules associated with costameres and
CC neuromuscular junctions (By similarity). Attaches integral
CC membrane proteins to cytoskeletal elements. Also binds to
CC cytoskeletal proteins. Required for coordinate assembly of Na/Ca
CC exchanger, Na/K ATPase and InsP3 receptor at sarcoplasmic
CC reticulum sites in cardiomyocytes. Required for the coordinated
CC expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin
CC (SPTBN1) in the inner segment of rod photoreceptors. Required for
CC expression and targeting of SPTBN1 in neonatal cardiomyocytes and
CC for the regulation of neonatal cardiomyocyte contraction rate.
CC -!- SUBUNIT: Directly interacts with DMD; this interaction is
CC necessary for DMD localization at the sarcolemma. Interacts with
CC DCTN4; this interaction is required for DCTN4 retention at
CC costameres (By similarity). Interacts with RHBG and SPTBN1.
CC -!- INTERACTION:
CC P11532-5:DMD; NbExp=2; IntAct=EBI-941975, EBI-1018651;
CC P62993:GRB2; NbExp=2; IntAct=EBI-941975, EBI-401755;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Membrane.
CC Cytoplasm, myofibril, sarcomere, M line (By similarity). Apical
CC cell membrane (By similarity). Cell membrane. Cell junction,
CC synapse, postsynaptic cell membrane (By similarity).
CC Note=Expressed at the apical membrane of airway lung epithelial
CC cells (By similarity). Localized to the plasma membrane of the
CC inner segments of photoreceptors in retina. Colocalizes with
CC SPTBN1 in a distict intracellular compartment of neonatal
CC cardiomyocytes (By similarity). In skeletal muscle, localizes to
CC neuromuscular junctions (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=3;
CC IsoId=Q01484-4; Sequence=Displayed;
CC Name=2;
CC IsoId=Q01484-2; Sequence=VSP_000268;
CC Name=4;
CC IsoId=Q01484-5; Sequence=VSP_037058, VSP_037059, VSP_000268;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q01484-7; Sequence=VSP_037057, VSP_000268, VSP_037060;
CC -!- TISSUE SPECIFICITY: Present in plasma membrane of neurons as well
CC as glial cells throughout the brain. Expressed in fetal brain and
CC in temporal cortex of adult brain. Also expressed in the inner
CC segments of rod photoreceptors in retina.
CC -!- DOMAIN: The tandem configuration of the two ZU5 and the UPA
CC domains forms a structural supramodule termed ZZU. ZU5-1 mediates
CC interaction with beta-spectrin, and the ZU5-1/UPA interface is
CC required for ankyrin's function other than binding to spectrin.
CC -!- PTM: Phosphorylated at multiple sites by different protein kinases
CC and each phosphorylation event regulates the protein's structure
CC and function (Potential).
CC -!- DISEASE: Long QT syndrome 4 (LQT4) [MIM:600919]: A heart disorder
CC characterized by a prolonged QT interval on the ECG and
CC polymorphic ventricular arrhythmias. They cause syncope and sudden
CC death in response to exercise or emotional stress, and can present
CC with a sentinel event of sudden cardiac death in infancy. Long QT
CC syndrome type 4 shows many atypical features compared to classical
CC long QT syndromes, including pronounced sinus bradycardia,
CC polyphasic T waves and atrial fibrillation. Cardiac repolarization
CC defects may be not as severe as in classical LQT syndromes and
CC prolonged QT interval on EKG is not a consistent feature. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Contains 24 ANK repeats.
CC -!- SIMILARITY: Contains 2 death domains.
CC -!- SIMILARITY: Contains 2 ZU5 domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAI25237.1; Type=Frameshift; Positions=1405;
CC Sequence=CAB42644.1; Type=Miscellaneous discrepancy; Note=CDS lacks C-terminal region which is nevertheless present in the underlying cDNA;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ANK2";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ankyrin entry;
CC URL="http://en.wikipedia.org/wiki/Ankyrin";
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DR EMBL; X56957; CAA40278.1; -; mRNA.
DR EMBL; X56958; CAA40279.2; -; mRNA.
DR EMBL; Z26634; CAB42644.1; ALT_SEQ; mRNA.
DR EMBL; BX537758; CAD97827.1; -; mRNA.
DR EMBL; AC004057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093617; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093879; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093900; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC125235; AAI25236.1; -; mRNA.
DR EMBL; BC125236; AAI25237.1; ALT_FRAME; mRNA.
DR EMBL; M37123; AAA62828.1; -; Genomic_DNA.
DR PIR; S37431; S37431.
DR RefSeq; NP_001120965.1; NM_001127493.1.
DR RefSeq; NP_001139.3; NM_001148.4.
DR RefSeq; NP_066187.2; NM_020977.3.
DR UniGene; Hs.620557; -.
DR PDB; 4D8O; X-ray; 2.20 A; A=966-3653.
DR PDBsum; 4D8O; -.
DR DisProt; DP00467; -.
DR ProteinModelPortal; Q01484; -.
DR SMR; Q01484; 432-841, 3570-3647.
DR DIP; DIP-37425N; -.
DR IntAct; Q01484; 16.
DR STRING; 9606.ENSP00000349588; -.
DR TCDB; 8.A.28.1.1; the ankyrin (ankyrin) family.
DR PhosphoSite; Q01484; -.
DR DMDM; 215274185; -.
DR PaxDb; Q01484; -.
DR PRIDE; Q01484; -.
DR Ensembl; ENST00000357077; ENSP00000349588; ENSG00000145362.
DR Ensembl; ENST00000394537; ENSP00000378044; ENSG00000145362.
DR Ensembl; ENST00000506722; ENSP00000421067; ENSG00000145362.
DR Ensembl; ENST00000510275; ENSP00000421023; ENSG00000145362.
DR GeneID; 287; -.
DR KEGG; hsa:287; -.
DR UCSC; uc003ibe.4; human.
DR CTD; 287; -.
DR GeneCards; GC04P113739; -.
DR H-InvDB; HIX0164018; -.
DR HGNC; HGNC:493; ANK2.
DR MIM; 106410; gene.
DR MIM; 600919; phenotype.
DR neXtProt; NX_Q01484; -.
DR Orphanet; 101016; Romano-Ward syndrome.
DR PharmGKB; PA24799; -.
DR eggNOG; COG0666; -.
DR HOGENOM; HOG000169277; -.
DR HOVERGEN; HBG100442; -.
DR KO; K10380; -.
DR PhylomeDB; Q01484; -.
DR Reactome; REACT_111045; Developmental Biology.
DR ChiTaRS; Ank2; human.
DR GenomeRNAi; 287; -.
DR NextBio; 1169; -.
DR PRO; PR:Q01484; -.
DR ArrayExpress; Q01484; -.
DR Bgee; Q01484; -.
DR CleanEx; HS_ANK2; -.
DR Genevestigator; Q01484; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0043034; C:costamere; ISS:BHF-UCL.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005887; C:integral to plasma membrane; IEA:Ensembl.
DR GO; GO:0014704; C:intercalated disc; ISS:BHF-UCL.
DR GO; GO:0031430; C:M band; ISS:BHF-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030315; C:T-tubule; ISS:BHF-UCL.
DR GO; GO:0030018; C:Z disc; ISS:BHF-UCL.
DR GO; GO:0051117; F:ATPase binding; ISS:BHF-UCL.
DR GO; GO:0044325; F:ion channel binding; ISS:BHF-UCL.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:Ensembl.
DR GO; GO:0030674; F:protein binding, bridging; ISS:BHF-UCL.
DR GO; GO:0003283; P:atrial septum development; IMP:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; ISS:BHF-UCL.
DR GO; GO:0086046; P:membrane depolarization involved in regulation of SA node cell action potential; TAS:BHF-UCL.
DR GO; GO:1901021; P:positive regulation of calcium ion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; ISS:BHF-UCL.
DR GO; GO:2001259; P:positive regulation of cation channel activity; ISS:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IGI:BHF-UCL.
DR GO; GO:1901018; P:positive regulation of potassium ion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:BHF-UCL.
DR GO; GO:0034394; P:protein localization to cell surface; ISS:BHF-UCL.
DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; IGI:BHF-UCL.
DR GO; GO:0036309; P:protein localization to M-band; ISS:BHF-UCL.
DR GO; GO:0036371; P:protein localization to T-tubule; ISS:BHF-UCL.
DR GO; GO:0050821; P:protein stabilization; ISS:BHF-UCL.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IEA:Ensembl.
DR GO; GO:0086014; P:regulation of atrial cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0010881; P:regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; IGI:BHF-UCL.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0086005; P:regulation of ventricular cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0060307; P:regulation of ventricular cardiac muscle cell membrane repolarization; IMP:BHF-UCL.
DR GO; GO:0070296; P:sarcoplasmic reticulum calcium ion transport; TAS:BHF-UCL.
DR GO; GO:0033292; P:T-tubule organization; ISS:BHF-UCL.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 1.25.40.20; -; 3.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR000906; ZU5.
DR Pfam; PF00023; Ank; 19.
DR Pfam; PF12796; Ank_2; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00791; ZU5; 2.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 23.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF48403; SSF48403; 3.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 20.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS51145; ZU5; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ANK repeat; Cell junction;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton;
KW Disease mutation; Long QT syndrome; Membrane; Phosphoprotein;
KW Polymorphism; Postsynaptic cell membrane; Reference proteome; Repeat;
KW Synapse.
FT CHAIN 1 3957 Ankyrin-2.
FT /FTId=PRO_0000066885.
FT REPEAT 30 62 ANK 1.
FT REPEAT 63 92 ANK 2.
FT REPEAT 96 125 ANK 3.
FT REPEAT 129 158 ANK 4.
FT REPEAT 162 191 ANK 5.
FT REPEAT 193 220 ANK 6.
FT REPEAT 232 261 ANK 7.
FT REPEAT 265 294 ANK 8.
FT REPEAT 298 327 ANK 9.
FT REPEAT 331 360 ANK 10.
FT REPEAT 364 393 ANK 11.
FT REPEAT 397 426 ANK 12.
FT REPEAT 430 459 ANK 13.
FT REPEAT 463 492 ANK 14.
FT REPEAT 496 525 ANK 15.
FT REPEAT 529 558 ANK 16.
FT REPEAT 562 591 ANK 17.
FT REPEAT 595 624 ANK 18.
FT REPEAT 628 657 ANK 19.
FT REPEAT 661 690 ANK 20.
FT REPEAT 694 723 ANK 21.
FT REPEAT 727 756 ANK 22.
FT REPEAT 760 789 ANK 23.
FT REPEAT 793 822 ANK 24.
FT DOMAIN 966 1124 ZU5 1.
FT DOMAIN 1125 1288 ZU5 2.
FT DOMAIN 1450 1535 Death 1.
FT REPEAT 1806 1817 Repeat A.
FT REPEAT 1818 1829 Repeat A.
FT REPEAT 1830 1841 Repeat A.
FT REPEAT 1842 1853 Repeat A.
FT REPEAT 1854 1865 Repeat A.
FT REPEAT 1866 1877 Repeat A.
FT REPEAT 1878 1889 Repeat A.
FT REPEAT 1890 1900 Repeat A; approximate.
FT REPEAT 1901 1912 Repeat A.
FT REPEAT 1913 1924 Repeat A.
FT REPEAT 1925 1935 Repeat A; approximate.
FT REPEAT 1936 1947 Repeat A.
FT REPEAT 1948 1959 Repeat A.
FT REPEAT 1960 1971 Repeat A.
FT REPEAT 1972 1983 Repeat A.
FT DOMAIN 3569 3653 Death 2.
FT REGION 966 1125 Interaction with SPTBN1.
FT REGION 1289 1423 UPA domain.
FT REGION 1806 1983 Repeat-rich region.
FT MOD_RES 378 378 Phosphotyrosine (By similarity).
FT MOD_RES 531 531 Phosphotyrosine (By similarity).
FT MOD_RES 1382 1382 Phosphotyrosine (By similarity).
FT MOD_RES 3776 3776 Phosphothreonine (By similarity).
FT VAR_SEQ 1 1348 Missing (in isoform 5).
FT /FTId=VSP_037057.
FT VAR_SEQ 1 27 MMNEDAAQKSDSGEKFNGSSQRRKRPK -> MTTMLQ (in
FT isoform 4).
FT /FTId=VSP_037058.
FT VAR_SEQ 967 967 G -> GRASPCLERDNSS (in isoform 4).
FT /FTId=VSP_037059.
FT VAR_SEQ 1477 3561 Missing (in isoform 2, isoform 4 and
FT isoform 5).
FT /FTId=VSP_000268.
FT VAR_SEQ 3870 3870 K -> KELTEELGELEASSDEEAMVTTRVVRRRVIIQ (in
FT isoform 5).
FT /FTId=VSP_037060.
FT VARIANT 685 685 G -> E (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035606.
FT VARIANT 687 687 N -> S (in dbSNP:rs29372).
FT /FTId=VAR_055504.
FT VARIANT 1267 1267 G -> R (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035607.
FT VARIANT 1458 1458 E -> G (in LQT4; loss of function;
FT dbSNP:rs72544141).
FT /FTId=VAR_022934.
FT VARIANT 2369 2369 V -> A (in dbSNP:rs28377576).
FT /FTId=VAR_055505.
FT VARIANT 3653 3653 T -> K (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035608.
FT VARIANT 3740 3740 L -> I (in LQT4; loss of function;
FT dbSNP:rs35530544).
FT /FTId=VAR_022935.
FT VARIANT 3744 3744 T -> N (in LQT4; loss of function).
FT /FTId=VAR_022936.
FT VARIANT 3906 3906 R -> W (in LQT4; loss of function;
FT dbSNP:rs121912706).
FT /FTId=VAR_022937.
FT VARIANT 3931 3931 E -> K (in LQT4; loss of function;
FT dbSNP:rs45454496).
FT /FTId=VAR_022938.
FT MUTAGEN 975 977 DAR->AAA: Prevents binding to SPTBN1.
FT MUTAGEN 1000 1000 A->P: Prevents binding to SPTBN1.
FT MUTAGEN 1100 1103 ENGD->AAGA: Weak binding to SPTBN1.
FT CONFLICT 220 220 V -> I (in Ref. 4; CAD97827).
FT CONFLICT 475 476 GQ -> PE (in Ref. 7; AAA62828).
FT CONFLICT 2787 2787 A -> R (in Ref. 3; CAB42644).
FT CONFLICT 2999 2999 Q -> L (in Ref. 3; CAB42644).
FT CONFLICT 3140 3141 EE -> RY (in Ref. 5; AC093879).
FT CONFLICT 3185 3185 D -> S (in Ref. 3; CAB42644).
FT CONFLICT 3699 3699 V -> A (in Ref. 4; CAD97827).
FT CONFLICT 3737 3737 A -> S (in Ref. 1; CAA40279 and 3;
FT CAB42644).
FT CONFLICT 3955 3956 NN -> SM (in Ref. 5; AC093879).
FT STRAND 969 974
FT STRAND 979 982
FT STRAND 984 986
FT STRAND 990 993
FT STRAND 1002 1009
FT STRAND 1025 1028
FT STRAND 1031 1035
FT STRAND 1039 1042
FT STRAND 1076 1082
FT TURN 1088 1091
FT STRAND 1092 1103
FT HELIX 1131 1137
FT STRAND 1139 1146
FT STRAND 1149 1157
FT STRAND 1159 1165
FT STRAND 1168 1172
FT STRAND 1174 1176
FT STRAND 1180 1183
FT STRAND 1192 1199
FT HELIX 1203 1210
FT STRAND 1213 1216
FT STRAND 1219 1226
FT STRAND 1228 1238
FT STRAND 1258 1263
FT HELIX 1277 1279
FT STRAND 1283 1285
FT STRAND 1288 1295
FT STRAND 1298 1305
FT HELIX 1307 1309
FT HELIX 1310 1321
FT STRAND 1325 1335
FT STRAND 1338 1349
FT HELIX 1357 1359
FT STRAND 1365 1369
FT STRAND 1373 1376
FT STRAND 1380 1391
FT STRAND 1399 1402
FT STRAND 1410 1418
FT STRAND 1424 1432
FT STRAND 1445 1451
SQ SEQUENCE 3957 AA; 433715 MW; 41C1A240CC5A3B72 CRC64;
MMNEDAAQKS DSGEKFNGSS QRRKRPKKSD SNASFLRAAR AGNLDKVVEY LKGGIDINTC
NQNGLNALHL AAKEGHVGLV QELLGRGSSV DSATKKGNTA LHIASLAGQA EVVKVLVKEG
ANINAQSQNG FTPLYMAAQE NHIDVVKYLL ENGANQSTAT EDGFTPLAVA LQQGHNQAVA
ILLENDTKGK VRLPALHIAA RKDDTKSAAL LLQNDHNADV QSKMMVNRTT ESGFTPLHIA
AHYGNVNVAT LLLNRGAAVD FTARNGITPL HVASKRGNTN MVKLLLDRGG QIDAKTRDGL
TPLHCAARSG HDQVVELLLE RGAPLLARTK NGLSPLHMAA QGDHVECVKH LLQHKAPVDD
VTLDYLTALH VAAHCGHYRV TKLLLDKRAN PNARALNGFT PLHIACKKNR IKVMELLVKY
GASIQAITES GLTPIHVAAF MGHLNIVLLL LQNGASPDVT NIRGETALHM AARAGQVEVV
RCLLRNGALV DARAREEQTP LHIASRLGKT EIVQLLLQHM AHPDAATTNG YTPLHISARE
GQVDVASVLL EAGAAHSLAT KKGFTPLHVA AKYGSLDVAK LLLQRRAAAD SAGKNGLTPL
HVAAHYDNQK VALLLLEKGA SPHATAKNGY TPLHIAAKKN QMQIASTLLN YGAETNIVTK
QGVTPLHLAS QEGHTDMVTL LLDKGANIHM STKSGLTSLH LAAQEDKVNV ADILTKHGAD
QDAHTKLGYT PLIVACHYGN VKMVNFLLKQ GANVNAKTKN GYTPLHQAAQ QGHTHIINVL
LQHGAKPNAT TANGNTALAI AKRLGYISVV DTLKVVTEEV TTTTTTITEK HKLNVPETMT
EVLDVSDEEG DDTMTGDGGE YLRPEDLKEL GDDSLPSSQF LDGMNYLRYS LEGGRSDSLR
SFSSDRSHTL SHASYLRDSA VMDDSVVIPS HQVSTLAKEA ERNSYRLSWG TENLDNVALS
SSPIHSGFLV SFMVDARGGA MRGCRHNGLR IIIPPRKCTA PTRVTCRLVK RHRLATMPPM
VEGEGLASRL IEVGPSGAQF LGKLHLPTAP PPLNEGESLV SRILQLGPPG TKFLGPVIVE
IPHFAALRGK ERELVVLRSE NGDSWKEHFC DYTEDELNEI LNGMDEVLDS PEDLEKKRIC
RIITRDFPQY FAVVSRIKQD SNLIGPEGGV LSSTVVPQVQ AVFPEGALTK RIRVGLQAQP
MHSELVKKIL GNKATFSPIV TLEPRRRKFH KPITMTIPVP KASSDVMLNG FGGDAPTLRL
LCSITGGTTP AQWEDITGTT PLTFVNECVS FTTNVSARFW LIDCRQIQES VTFASQVYRE
IICVPYMAKF VVFAKSHDPI EARLRCFCMT DDKVDKTLEQ QENFAEVARS RDVEVLEGKP
IYVDCFGNLV PLTKSGQHHI FSFFAFKENR LPLFVKVRDT TQEPCGRLSF MKEPKSTRGL
VHQAICNLNI TLPIYTKESE SDQEQEEEID MTSEKNDETE STETSVLKSH LVNEVPVLAS
PDLLSEVSEM KQDLIKMTAI LTTDVSDKAG SIKVKELVKA AEEEPGEPFE IVERVKEDLE
KVNEILRSGT CTRDESSVQS SRSERGLVEE EWVIVSDEEI EEARQKAPLE ITEYPCVEVR
IDKEIKGKVE KDSTGLVNYL TDDLNTCVPL PKEQLQTVQD KAGKKCEALA VGRSSEKEGK
DIPPDETQST QKQHKPSLGI KKPVRRKLKE KQKQKEEGLQ ASAEKAELKK GSSEESLGED
PGLAPEPLPT VKATSPLIEE TPIGSIKDKV KALQKRVEDE QKGRSKLPIR VKGKEDVPKK
TTHRPHPAAS PSLKSERHAP GSPSPKTERH STLSSSAKTE RHPPVSPSSK TEKHSPVSPS
AKTERHSPAS SSSKTEKHSP VSPSTKTERH SPVSSTKTER HPPVSPSGKT DKRPPVSPSG
RTEKHPPVSP GRTEKRLPVS PSGRTDKHQP VSTAGKTEKH LPVSPSGKTE KQPPVSPTSK
TERIEETMSV RELMKAFQSG QDPSKHKTGL FEHKSAKQKQ PQEKGKVRVE KEKGPILTQR
EAQKTENQTI KRGQRLPVTG TAESKRGVRV SSIGVKKEDA AGGKEKVLSH KIPEPVQSVP
EEESHRESEV PKEKMADEQG DMDLQISPDR KTSTDFSEVI KQELEDNDKY QQFRLSEETE
KAQLHLDQVL TSPFNTTFPL DYMKDEFLPA LSLQSGALDG SSESLKNEGV AGSPCGSLME
GTPQISSEES YKHEGLAETP ETSPESLSFS PKKSEEQTGE TKESTKTETT TEIRSEKEHP
TTKDITGGSE ERGATVTEDS ETSTESFQKE ATLGSPKDTS PKRQDDCTGS CSVALAKETP
TGLTEEAACD EGQRTFGSSA HKTQTDSEVQ ESTATSDETK ALPLPEASVK TDTGTESKPQ
GVIRSPQGLE LALPSRDSEV LSAVADDSLA VSHKDSLEAS PVLEDNSSHK TPDSLEPSPL
KESPCRDSLE SSPVEPKMKA GIFPSHFPLP AAVAKTELLT EVASVRSRLL RDPDGSAEDD
SLEQTSLMES SGKSPLSPDT PSSEEVSYEV TPKTTDVSTP KPAVIHECAE EDDSENGEKK
RFTPEEEMFK MVTKIKMFDE LEQEAKQKRD YKKEPKQEES SSSSDPDADC SVDVDEPKHT
GSGEDESGVP VLVTSESRKV SSSSESEPEL AQLKKGADSG LLPEPVIRVQ PPSPLPSSMD
SNSSPEEVQF QPVVSKQYTF KMNEDTQEEP GKSEEEKDSE SHLAEDRHAV STEAEDRSYD
KLNRDTDQPK ICDGHGCEAM SPSSSAAPVS SGLQSPTGDD VDEQPVIYKE SLALQGTHEK
DTEGEELDVS RAESPQADCP SESFSSSSSL PHCLVSEGKE LDEDISATSS IQKTEVTKTD
ETFENLPKDC PSQDSSITTQ TDRFSMDVPV SDLAENDEIY DPQITSPYEN VPSQSFFSSE
ESKTQTDANH TTSFHSSEVY SVTITSPVED VVVASSSSGT VLSKESNFEG QDIKMESQQE
STLWEMQSDS VSSSFEPTMS ATTTVVGEQI SKVIITKTDV DSDSWSEIRE DDEAFEARVK
EEEQKIFGLM VDRQSQGTTP DTTPARTPTE EGTPTSEQNP FLFQEGKLFE MTRSGAIDMT
KRSYADESFH FFQIGQESRE ETLSEDVKEG ATGADPLPLE TSAESLALSE SKETVDDEAD
LLPDDVSEEV EEIPASDAQL NSQMGISAST ETPTKEAVSV GTKDLPTVQT GDIPPLSGVK
QISCPDSSEP AVQVQLDFST LTRSVYSDRG DDSPDSSPEE QKSVIEIPTA PMENVPFTES
KSKIPVRTMP TSTPAPPSAE YESSVSEDFL SSVDEENKAD EAKPKSKLPV KVPLQRVEQQ
LSDLDTSVQK TVAPQGQDMA SIAPDNRSKS ESDASSLDSK TKCPVKTRSY TETETESRER
AEELELESEE GATRPKILTS RLPVKSRSTT SSCRGGTSPT KESKEHFFDL YRNSIEFFEE
ISDEASKLVD RLTQSEREQE IVSDDESSSA LEVSVIENLP PVETEHSVPE DIFDTRPIWD
ESIETLIERI PDENGHDHAE DPQDEQERIE ERLAYIADHL GFSWTELARE LDFTEEQIHQ
IRIENPNSLQ DQSHALLKYW LERDGKHATD TNLVECLTKI NRMDIVHLME TNTEPLQERI
SHSYAEIEQT ITLDHSEGFS VLQEELCTAQ HKQKEEQAVS KESETCDHPP IVSEEDISVG
YSTFQDGVPK TEGDSSATAL FPQTHKEQVQ QDFSGKMQDL PEESSLEYQQ EYFVTTPGTE
TSETQKAMIV PSSPSKTPEE VSTPAEEEKL YLQTPTSSER GGSPIIQEPE EPSEHREESS
PRKTSLVIVE SADNQPETCE RLDEDAAFEK GDDMPEIPPE TVTEEEYIDE HGHTVVKKVT
RKIIRRYVSS EGTEKEEIMV QGMPQEPVNI EEGDGYSKVI KRVVLKSDTE QSEDNNE
//
ID ANK2_HUMAN Reviewed; 3957 AA.
AC Q01484; Q01485; Q08AC7; Q08AC8; Q7Z3L5;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-MAY-2012, sequence version 4.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=Ankyrin-2;
DE Short=ANK-2;
DE AltName: Full=Ankyrin-B;
DE AltName: Full=Brain ankyrin;
DE AltName: Full=Non-erythroid ankyrin;
GN Name=ANK2;
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] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 1477-2110 (ISOFORM 3), AND TISSUE SPECIFICITY.
RC TISSUE=Brain stem;
RX PubMed=1830053; DOI=10.1083/jcb.114.2.241;
RA Otto E., Kunimoto M., McLaughlin T., Bennett V.;
RT "Isolation and characterization of cDNAs encoding human brain ankyrins
RT reveal a family of alternatively spliced genes.";
RL J. Cell Biol. 114:241-253(1991).
RN [2]
RP SEQUENCE REVISION.
RA Carpenter S.;
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Brain stem;
RX PubMed=8253844; DOI=10.1083/jcb.123.6.1463;
RA Chan W., Kordeli E., Bennett V.;
RT "440-kD ankyrinB: structure of the major developmentally regulated
RT domain and selective localization in unmyelinated axons.";
RL J. Cell Biol. 123:1463-1473(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 463-495, AND TISSUE SPECIFICITY.
RX PubMed=1833308; DOI=10.1016/0888-7543(91)90173-C;
RA Tse W.T., Menninger J.C., Yang-Feng T.L., Francke U., Sahr K.E.,
RA Lux S.E., Ward D.C., Forget B.G.;
RT "Isolation and chromosomal localization of a novel nonerythroid
RT ankyrin gene.";
RL Genomics 10:858-866(1991).
RN [8]
RP FUNCTION, AND VARIANT LQT4 GLY-1458.
RX PubMed=12571597; DOI=10.1038/nature01335;
RA Mohler P.J., Schott J.-J., Gramolini A.O., Dilly K.W., Guatimosim S.,
RA duBell W.H., Song L.-S., Haurogne K., Kyndt F., Ali M.E., Rogers T.B.,
RA Lederer W.J., Escande D., Le Marec H., Bennett V.;
RT "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
RT sudden cardiac death.";
RL Nature 421:634-639(2003).
RN [9]
RP INTERACTION WITH SPTBN1, AND MUTAGENESIS OF 975-ASP--ARG-977; ALA-1000
RP AND 1100-GLU--ASP-1103.
RX PubMed=15262991; DOI=10.1074/jbc.M406018200;
RA Mohler P.J., Yoon W., Bennett V.;
RT "Ankyrin-B targets beta2-spectrin to an intracellular compartment in
RT neonatal cardiomyocytes.";
RL J. Biol. Chem. 279:40185-40193(2004).
RN [10]
RP INTERACTION WITH RHBG.
RX PubMed=15611082; DOI=10.1074/jbc.M413351200;
RA Lopez C., Metral S., Eladari D., Drevensek S., Gane P., Chambrey R.,
RA Bennett V., Cartron J.-P., Le Van Kim C., Colin Y.;
RT "The ammonium transporter RhBG: requirement of a tyrosine-based signal
RT and ankyrin-G for basolateral targeting and membrane anchorage in
RT polarized kidney epithelial cells.";
RL J. Biol. Chem. 280:8221-8228(2005).
RN [11]
RP SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=19007774; DOI=10.1016/j.exer.2008.09.022;
RA Kizhatil K., Sandhu N.K., Peachey N.S., Bennett V.;
RT "Ankyrin-B is required for coordinated expression of beta-2-spectrin,
RT the Na/K-ATPase and the Na/Ca exchanger in the inner segment of rod
RT photoreceptors.";
RL Exp. Eye Res. 88:57-64(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 966-3620, DOMAIN DEATH 1,
RP DOMAIN UPA, AND DOMAINS ZU5.
RX PubMed=22411828; DOI=10.1073/pnas.1200613109;
RA Wang C., Yu C., Ye F., Wei Z., Zhang M.;
RT "Structure of the ZU5-ZU5-UPA-DD tandem of ankyrin-B reveals
RT interaction surfaces necessary for ankyrin function.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:4822-4827(2012).
RN [15]
RP VARIANTS LQT4 GLY-1458; ILE-3740; ASN-3744; TRP-3906 AND LYS-3931, AND
RP CHARACTERIZATION OF VARIANTS LQT4.
RX PubMed=15178757; DOI=10.1073/pnas.0402546101;
RA Mohler P.J., Splawski I., Napolitano C., Bottelli G., Sharpe L.,
RA Timothy K., Priori S.G., Keating M.T., Bennett V.;
RT "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:9137-9142(2004).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] GLU-685; ARG-1267 AND LYS-3653.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: In skeletal muscle, required for proper localization of
CC DMD and DCTN4 and for the formation and/or stability of a special
CC subset of microtubules associated with costameres and
CC neuromuscular junctions (By similarity). Attaches integral
CC membrane proteins to cytoskeletal elements. Also binds to
CC cytoskeletal proteins. Required for coordinate assembly of Na/Ca
CC exchanger, Na/K ATPase and InsP3 receptor at sarcoplasmic
CC reticulum sites in cardiomyocytes. Required for the coordinated
CC expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin
CC (SPTBN1) in the inner segment of rod photoreceptors. Required for
CC expression and targeting of SPTBN1 in neonatal cardiomyocytes and
CC for the regulation of neonatal cardiomyocyte contraction rate.
CC -!- SUBUNIT: Directly interacts with DMD; this interaction is
CC necessary for DMD localization at the sarcolemma. Interacts with
CC DCTN4; this interaction is required for DCTN4 retention at
CC costameres (By similarity). Interacts with RHBG and SPTBN1.
CC -!- INTERACTION:
CC P11532-5:DMD; NbExp=2; IntAct=EBI-941975, EBI-1018651;
CC P62993:GRB2; NbExp=2; IntAct=EBI-941975, EBI-401755;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Membrane.
CC Cytoplasm, myofibril, sarcomere, M line (By similarity). Apical
CC cell membrane (By similarity). Cell membrane. Cell junction,
CC synapse, postsynaptic cell membrane (By similarity).
CC Note=Expressed at the apical membrane of airway lung epithelial
CC cells (By similarity). Localized to the plasma membrane of the
CC inner segments of photoreceptors in retina. Colocalizes with
CC SPTBN1 in a distict intracellular compartment of neonatal
CC cardiomyocytes (By similarity). In skeletal muscle, localizes to
CC neuromuscular junctions (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=3;
CC IsoId=Q01484-4; Sequence=Displayed;
CC Name=2;
CC IsoId=Q01484-2; Sequence=VSP_000268;
CC Name=4;
CC IsoId=Q01484-5; Sequence=VSP_037058, VSP_037059, VSP_000268;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q01484-7; Sequence=VSP_037057, VSP_000268, VSP_037060;
CC -!- TISSUE SPECIFICITY: Present in plasma membrane of neurons as well
CC as glial cells throughout the brain. Expressed in fetal brain and
CC in temporal cortex of adult brain. Also expressed in the inner
CC segments of rod photoreceptors in retina.
CC -!- DOMAIN: The tandem configuration of the two ZU5 and the UPA
CC domains forms a structural supramodule termed ZZU. ZU5-1 mediates
CC interaction with beta-spectrin, and the ZU5-1/UPA interface is
CC required for ankyrin's function other than binding to spectrin.
CC -!- PTM: Phosphorylated at multiple sites by different protein kinases
CC and each phosphorylation event regulates the protein's structure
CC and function (Potential).
CC -!- DISEASE: Long QT syndrome 4 (LQT4) [MIM:600919]: A heart disorder
CC characterized by a prolonged QT interval on the ECG and
CC polymorphic ventricular arrhythmias. They cause syncope and sudden
CC death in response to exercise or emotional stress, and can present
CC with a sentinel event of sudden cardiac death in infancy. Long QT
CC syndrome type 4 shows many atypical features compared to classical
CC long QT syndromes, including pronounced sinus bradycardia,
CC polyphasic T waves and atrial fibrillation. Cardiac repolarization
CC defects may be not as severe as in classical LQT syndromes and
CC prolonged QT interval on EKG is not a consistent feature. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Contains 24 ANK repeats.
CC -!- SIMILARITY: Contains 2 death domains.
CC -!- SIMILARITY: Contains 2 ZU5 domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAI25237.1; Type=Frameshift; Positions=1405;
CC Sequence=CAB42644.1; Type=Miscellaneous discrepancy; Note=CDS lacks C-terminal region which is nevertheless present in the underlying cDNA;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ANK2";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ankyrin entry;
CC URL="http://en.wikipedia.org/wiki/Ankyrin";
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DR EMBL; X56957; CAA40278.1; -; mRNA.
DR EMBL; X56958; CAA40279.2; -; mRNA.
DR EMBL; Z26634; CAB42644.1; ALT_SEQ; mRNA.
DR EMBL; BX537758; CAD97827.1; -; mRNA.
DR EMBL; AC004057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093617; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093879; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093900; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC125235; AAI25236.1; -; mRNA.
DR EMBL; BC125236; AAI25237.1; ALT_FRAME; mRNA.
DR EMBL; M37123; AAA62828.1; -; Genomic_DNA.
DR PIR; S37431; S37431.
DR RefSeq; NP_001120965.1; NM_001127493.1.
DR RefSeq; NP_001139.3; NM_001148.4.
DR RefSeq; NP_066187.2; NM_020977.3.
DR UniGene; Hs.620557; -.
DR PDB; 4D8O; X-ray; 2.20 A; A=966-3653.
DR PDBsum; 4D8O; -.
DR DisProt; DP00467; -.
DR ProteinModelPortal; Q01484; -.
DR SMR; Q01484; 432-841, 3570-3647.
DR DIP; DIP-37425N; -.
DR IntAct; Q01484; 16.
DR STRING; 9606.ENSP00000349588; -.
DR TCDB; 8.A.28.1.1; the ankyrin (ankyrin) family.
DR PhosphoSite; Q01484; -.
DR DMDM; 215274185; -.
DR PaxDb; Q01484; -.
DR PRIDE; Q01484; -.
DR Ensembl; ENST00000357077; ENSP00000349588; ENSG00000145362.
DR Ensembl; ENST00000394537; ENSP00000378044; ENSG00000145362.
DR Ensembl; ENST00000506722; ENSP00000421067; ENSG00000145362.
DR Ensembl; ENST00000510275; ENSP00000421023; ENSG00000145362.
DR GeneID; 287; -.
DR KEGG; hsa:287; -.
DR UCSC; uc003ibe.4; human.
DR CTD; 287; -.
DR GeneCards; GC04P113739; -.
DR H-InvDB; HIX0164018; -.
DR HGNC; HGNC:493; ANK2.
DR MIM; 106410; gene.
DR MIM; 600919; phenotype.
DR neXtProt; NX_Q01484; -.
DR Orphanet; 101016; Romano-Ward syndrome.
DR PharmGKB; PA24799; -.
DR eggNOG; COG0666; -.
DR HOGENOM; HOG000169277; -.
DR HOVERGEN; HBG100442; -.
DR KO; K10380; -.
DR PhylomeDB; Q01484; -.
DR Reactome; REACT_111045; Developmental Biology.
DR ChiTaRS; Ank2; human.
DR GenomeRNAi; 287; -.
DR NextBio; 1169; -.
DR PRO; PR:Q01484; -.
DR ArrayExpress; Q01484; -.
DR Bgee; Q01484; -.
DR CleanEx; HS_ANK2; -.
DR Genevestigator; Q01484; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0043034; C:costamere; ISS:BHF-UCL.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005887; C:integral to plasma membrane; IEA:Ensembl.
DR GO; GO:0014704; C:intercalated disc; ISS:BHF-UCL.
DR GO; GO:0031430; C:M band; ISS:BHF-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030315; C:T-tubule; ISS:BHF-UCL.
DR GO; GO:0030018; C:Z disc; ISS:BHF-UCL.
DR GO; GO:0051117; F:ATPase binding; ISS:BHF-UCL.
DR GO; GO:0044325; F:ion channel binding; ISS:BHF-UCL.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:Ensembl.
DR GO; GO:0030674; F:protein binding, bridging; ISS:BHF-UCL.
DR GO; GO:0003283; P:atrial septum development; IMP:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; ISS:BHF-UCL.
DR GO; GO:0086046; P:membrane depolarization involved in regulation of SA node cell action potential; TAS:BHF-UCL.
DR GO; GO:1901021; P:positive regulation of calcium ion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; ISS:BHF-UCL.
DR GO; GO:2001259; P:positive regulation of cation channel activity; ISS:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IGI:BHF-UCL.
DR GO; GO:1901018; P:positive regulation of potassium ion transmembrane transporter activity; ISS:BHF-UCL.
DR GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:BHF-UCL.
DR GO; GO:0034394; P:protein localization to cell surface; ISS:BHF-UCL.
DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; IGI:BHF-UCL.
DR GO; GO:0036309; P:protein localization to M-band; ISS:BHF-UCL.
DR GO; GO:0036371; P:protein localization to T-tubule; ISS:BHF-UCL.
DR GO; GO:0050821; P:protein stabilization; ISS:BHF-UCL.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IEA:Ensembl.
DR GO; GO:0086014; P:regulation of atrial cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0010881; P:regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; IGI:BHF-UCL.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0086005; P:regulation of ventricular cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0060307; P:regulation of ventricular cardiac muscle cell membrane repolarization; IMP:BHF-UCL.
DR GO; GO:0070296; P:sarcoplasmic reticulum calcium ion transport; TAS:BHF-UCL.
DR GO; GO:0033292; P:T-tubule organization; ISS:BHF-UCL.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 1.25.40.20; -; 3.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR000906; ZU5.
DR Pfam; PF00023; Ank; 19.
DR Pfam; PF12796; Ank_2; 1.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00791; ZU5; 2.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 23.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF48403; SSF48403; 3.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 20.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS51145; ZU5; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ANK repeat; Cell junction;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton;
KW Disease mutation; Long QT syndrome; Membrane; Phosphoprotein;
KW Polymorphism; Postsynaptic cell membrane; Reference proteome; Repeat;
KW Synapse.
FT CHAIN 1 3957 Ankyrin-2.
FT /FTId=PRO_0000066885.
FT REPEAT 30 62 ANK 1.
FT REPEAT 63 92 ANK 2.
FT REPEAT 96 125 ANK 3.
FT REPEAT 129 158 ANK 4.
FT REPEAT 162 191 ANK 5.
FT REPEAT 193 220 ANK 6.
FT REPEAT 232 261 ANK 7.
FT REPEAT 265 294 ANK 8.
FT REPEAT 298 327 ANK 9.
FT REPEAT 331 360 ANK 10.
FT REPEAT 364 393 ANK 11.
FT REPEAT 397 426 ANK 12.
FT REPEAT 430 459 ANK 13.
FT REPEAT 463 492 ANK 14.
FT REPEAT 496 525 ANK 15.
FT REPEAT 529 558 ANK 16.
FT REPEAT 562 591 ANK 17.
FT REPEAT 595 624 ANK 18.
FT REPEAT 628 657 ANK 19.
FT REPEAT 661 690 ANK 20.
FT REPEAT 694 723 ANK 21.
FT REPEAT 727 756 ANK 22.
FT REPEAT 760 789 ANK 23.
FT REPEAT 793 822 ANK 24.
FT DOMAIN 966 1124 ZU5 1.
FT DOMAIN 1125 1288 ZU5 2.
FT DOMAIN 1450 1535 Death 1.
FT REPEAT 1806 1817 Repeat A.
FT REPEAT 1818 1829 Repeat A.
FT REPEAT 1830 1841 Repeat A.
FT REPEAT 1842 1853 Repeat A.
FT REPEAT 1854 1865 Repeat A.
FT REPEAT 1866 1877 Repeat A.
FT REPEAT 1878 1889 Repeat A.
FT REPEAT 1890 1900 Repeat A; approximate.
FT REPEAT 1901 1912 Repeat A.
FT REPEAT 1913 1924 Repeat A.
FT REPEAT 1925 1935 Repeat A; approximate.
FT REPEAT 1936 1947 Repeat A.
FT REPEAT 1948 1959 Repeat A.
FT REPEAT 1960 1971 Repeat A.
FT REPEAT 1972 1983 Repeat A.
FT DOMAIN 3569 3653 Death 2.
FT REGION 966 1125 Interaction with SPTBN1.
FT REGION 1289 1423 UPA domain.
FT REGION 1806 1983 Repeat-rich region.
FT MOD_RES 378 378 Phosphotyrosine (By similarity).
FT MOD_RES 531 531 Phosphotyrosine (By similarity).
FT MOD_RES 1382 1382 Phosphotyrosine (By similarity).
FT MOD_RES 3776 3776 Phosphothreonine (By similarity).
FT VAR_SEQ 1 1348 Missing (in isoform 5).
FT /FTId=VSP_037057.
FT VAR_SEQ 1 27 MMNEDAAQKSDSGEKFNGSSQRRKRPK -> MTTMLQ (in
FT isoform 4).
FT /FTId=VSP_037058.
FT VAR_SEQ 967 967 G -> GRASPCLERDNSS (in isoform 4).
FT /FTId=VSP_037059.
FT VAR_SEQ 1477 3561 Missing (in isoform 2, isoform 4 and
FT isoform 5).
FT /FTId=VSP_000268.
FT VAR_SEQ 3870 3870 K -> KELTEELGELEASSDEEAMVTTRVVRRRVIIQ (in
FT isoform 5).
FT /FTId=VSP_037060.
FT VARIANT 685 685 G -> E (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035606.
FT VARIANT 687 687 N -> S (in dbSNP:rs29372).
FT /FTId=VAR_055504.
FT VARIANT 1267 1267 G -> R (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035607.
FT VARIANT 1458 1458 E -> G (in LQT4; loss of function;
FT dbSNP:rs72544141).
FT /FTId=VAR_022934.
FT VARIANT 2369 2369 V -> A (in dbSNP:rs28377576).
FT /FTId=VAR_055505.
FT VARIANT 3653 3653 T -> K (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035608.
FT VARIANT 3740 3740 L -> I (in LQT4; loss of function;
FT dbSNP:rs35530544).
FT /FTId=VAR_022935.
FT VARIANT 3744 3744 T -> N (in LQT4; loss of function).
FT /FTId=VAR_022936.
FT VARIANT 3906 3906 R -> W (in LQT4; loss of function;
FT dbSNP:rs121912706).
FT /FTId=VAR_022937.
FT VARIANT 3931 3931 E -> K (in LQT4; loss of function;
FT dbSNP:rs45454496).
FT /FTId=VAR_022938.
FT MUTAGEN 975 977 DAR->AAA: Prevents binding to SPTBN1.
FT MUTAGEN 1000 1000 A->P: Prevents binding to SPTBN1.
FT MUTAGEN 1100 1103 ENGD->AAGA: Weak binding to SPTBN1.
FT CONFLICT 220 220 V -> I (in Ref. 4; CAD97827).
FT CONFLICT 475 476 GQ -> PE (in Ref. 7; AAA62828).
FT CONFLICT 2787 2787 A -> R (in Ref. 3; CAB42644).
FT CONFLICT 2999 2999 Q -> L (in Ref. 3; CAB42644).
FT CONFLICT 3140 3141 EE -> RY (in Ref. 5; AC093879).
FT CONFLICT 3185 3185 D -> S (in Ref. 3; CAB42644).
FT CONFLICT 3699 3699 V -> A (in Ref. 4; CAD97827).
FT CONFLICT 3737 3737 A -> S (in Ref. 1; CAA40279 and 3;
FT CAB42644).
FT CONFLICT 3955 3956 NN -> SM (in Ref. 5; AC093879).
FT STRAND 969 974
FT STRAND 979 982
FT STRAND 984 986
FT STRAND 990 993
FT STRAND 1002 1009
FT STRAND 1025 1028
FT STRAND 1031 1035
FT STRAND 1039 1042
FT STRAND 1076 1082
FT TURN 1088 1091
FT STRAND 1092 1103
FT HELIX 1131 1137
FT STRAND 1139 1146
FT STRAND 1149 1157
FT STRAND 1159 1165
FT STRAND 1168 1172
FT STRAND 1174 1176
FT STRAND 1180 1183
FT STRAND 1192 1199
FT HELIX 1203 1210
FT STRAND 1213 1216
FT STRAND 1219 1226
FT STRAND 1228 1238
FT STRAND 1258 1263
FT HELIX 1277 1279
FT STRAND 1283 1285
FT STRAND 1288 1295
FT STRAND 1298 1305
FT HELIX 1307 1309
FT HELIX 1310 1321
FT STRAND 1325 1335
FT STRAND 1338 1349
FT HELIX 1357 1359
FT STRAND 1365 1369
FT STRAND 1373 1376
FT STRAND 1380 1391
FT STRAND 1399 1402
FT STRAND 1410 1418
FT STRAND 1424 1432
FT STRAND 1445 1451
SQ SEQUENCE 3957 AA; 433715 MW; 41C1A240CC5A3B72 CRC64;
MMNEDAAQKS DSGEKFNGSS QRRKRPKKSD SNASFLRAAR AGNLDKVVEY LKGGIDINTC
NQNGLNALHL AAKEGHVGLV QELLGRGSSV DSATKKGNTA LHIASLAGQA EVVKVLVKEG
ANINAQSQNG FTPLYMAAQE NHIDVVKYLL ENGANQSTAT EDGFTPLAVA LQQGHNQAVA
ILLENDTKGK VRLPALHIAA RKDDTKSAAL LLQNDHNADV QSKMMVNRTT ESGFTPLHIA
AHYGNVNVAT LLLNRGAAVD FTARNGITPL HVASKRGNTN MVKLLLDRGG QIDAKTRDGL
TPLHCAARSG HDQVVELLLE RGAPLLARTK NGLSPLHMAA QGDHVECVKH LLQHKAPVDD
VTLDYLTALH VAAHCGHYRV TKLLLDKRAN PNARALNGFT PLHIACKKNR IKVMELLVKY
GASIQAITES GLTPIHVAAF MGHLNIVLLL LQNGASPDVT NIRGETALHM AARAGQVEVV
RCLLRNGALV DARAREEQTP LHIASRLGKT EIVQLLLQHM AHPDAATTNG YTPLHISARE
GQVDVASVLL EAGAAHSLAT KKGFTPLHVA AKYGSLDVAK LLLQRRAAAD SAGKNGLTPL
HVAAHYDNQK VALLLLEKGA SPHATAKNGY TPLHIAAKKN QMQIASTLLN YGAETNIVTK
QGVTPLHLAS QEGHTDMVTL LLDKGANIHM STKSGLTSLH LAAQEDKVNV ADILTKHGAD
QDAHTKLGYT PLIVACHYGN VKMVNFLLKQ GANVNAKTKN GYTPLHQAAQ QGHTHIINVL
LQHGAKPNAT TANGNTALAI AKRLGYISVV DTLKVVTEEV TTTTTTITEK HKLNVPETMT
EVLDVSDEEG DDTMTGDGGE YLRPEDLKEL GDDSLPSSQF LDGMNYLRYS LEGGRSDSLR
SFSSDRSHTL SHASYLRDSA VMDDSVVIPS HQVSTLAKEA ERNSYRLSWG TENLDNVALS
SSPIHSGFLV SFMVDARGGA MRGCRHNGLR IIIPPRKCTA PTRVTCRLVK RHRLATMPPM
VEGEGLASRL IEVGPSGAQF LGKLHLPTAP PPLNEGESLV SRILQLGPPG TKFLGPVIVE
IPHFAALRGK ERELVVLRSE NGDSWKEHFC DYTEDELNEI LNGMDEVLDS PEDLEKKRIC
RIITRDFPQY FAVVSRIKQD SNLIGPEGGV LSSTVVPQVQ AVFPEGALTK RIRVGLQAQP
MHSELVKKIL GNKATFSPIV TLEPRRRKFH KPITMTIPVP KASSDVMLNG FGGDAPTLRL
LCSITGGTTP AQWEDITGTT PLTFVNECVS FTTNVSARFW LIDCRQIQES VTFASQVYRE
IICVPYMAKF VVFAKSHDPI EARLRCFCMT DDKVDKTLEQ QENFAEVARS RDVEVLEGKP
IYVDCFGNLV PLTKSGQHHI FSFFAFKENR LPLFVKVRDT TQEPCGRLSF MKEPKSTRGL
VHQAICNLNI TLPIYTKESE SDQEQEEEID MTSEKNDETE STETSVLKSH LVNEVPVLAS
PDLLSEVSEM KQDLIKMTAI LTTDVSDKAG SIKVKELVKA AEEEPGEPFE IVERVKEDLE
KVNEILRSGT CTRDESSVQS SRSERGLVEE EWVIVSDEEI EEARQKAPLE ITEYPCVEVR
IDKEIKGKVE KDSTGLVNYL TDDLNTCVPL PKEQLQTVQD KAGKKCEALA VGRSSEKEGK
DIPPDETQST QKQHKPSLGI KKPVRRKLKE KQKQKEEGLQ ASAEKAELKK GSSEESLGED
PGLAPEPLPT VKATSPLIEE TPIGSIKDKV KALQKRVEDE QKGRSKLPIR VKGKEDVPKK
TTHRPHPAAS PSLKSERHAP GSPSPKTERH STLSSSAKTE RHPPVSPSSK TEKHSPVSPS
AKTERHSPAS SSSKTEKHSP VSPSTKTERH SPVSSTKTER HPPVSPSGKT DKRPPVSPSG
RTEKHPPVSP GRTEKRLPVS PSGRTDKHQP VSTAGKTEKH LPVSPSGKTE KQPPVSPTSK
TERIEETMSV RELMKAFQSG QDPSKHKTGL FEHKSAKQKQ PQEKGKVRVE KEKGPILTQR
EAQKTENQTI KRGQRLPVTG TAESKRGVRV SSIGVKKEDA AGGKEKVLSH KIPEPVQSVP
EEESHRESEV PKEKMADEQG DMDLQISPDR KTSTDFSEVI KQELEDNDKY QQFRLSEETE
KAQLHLDQVL TSPFNTTFPL DYMKDEFLPA LSLQSGALDG SSESLKNEGV AGSPCGSLME
GTPQISSEES YKHEGLAETP ETSPESLSFS PKKSEEQTGE TKESTKTETT TEIRSEKEHP
TTKDITGGSE ERGATVTEDS ETSTESFQKE ATLGSPKDTS PKRQDDCTGS CSVALAKETP
TGLTEEAACD EGQRTFGSSA HKTQTDSEVQ ESTATSDETK ALPLPEASVK TDTGTESKPQ
GVIRSPQGLE LALPSRDSEV LSAVADDSLA VSHKDSLEAS PVLEDNSSHK TPDSLEPSPL
KESPCRDSLE SSPVEPKMKA GIFPSHFPLP AAVAKTELLT EVASVRSRLL RDPDGSAEDD
SLEQTSLMES SGKSPLSPDT PSSEEVSYEV TPKTTDVSTP KPAVIHECAE EDDSENGEKK
RFTPEEEMFK MVTKIKMFDE LEQEAKQKRD YKKEPKQEES SSSSDPDADC SVDVDEPKHT
GSGEDESGVP VLVTSESRKV SSSSESEPEL AQLKKGADSG LLPEPVIRVQ PPSPLPSSMD
SNSSPEEVQF QPVVSKQYTF KMNEDTQEEP GKSEEEKDSE SHLAEDRHAV STEAEDRSYD
KLNRDTDQPK ICDGHGCEAM SPSSSAAPVS SGLQSPTGDD VDEQPVIYKE SLALQGTHEK
DTEGEELDVS RAESPQADCP SESFSSSSSL PHCLVSEGKE LDEDISATSS IQKTEVTKTD
ETFENLPKDC PSQDSSITTQ TDRFSMDVPV SDLAENDEIY DPQITSPYEN VPSQSFFSSE
ESKTQTDANH TTSFHSSEVY SVTITSPVED VVVASSSSGT VLSKESNFEG QDIKMESQQE
STLWEMQSDS VSSSFEPTMS ATTTVVGEQI SKVIITKTDV DSDSWSEIRE DDEAFEARVK
EEEQKIFGLM VDRQSQGTTP DTTPARTPTE EGTPTSEQNP FLFQEGKLFE MTRSGAIDMT
KRSYADESFH FFQIGQESRE ETLSEDVKEG ATGADPLPLE TSAESLALSE SKETVDDEAD
LLPDDVSEEV EEIPASDAQL NSQMGISAST ETPTKEAVSV GTKDLPTVQT GDIPPLSGVK
QISCPDSSEP AVQVQLDFST LTRSVYSDRG DDSPDSSPEE QKSVIEIPTA PMENVPFTES
KSKIPVRTMP TSTPAPPSAE YESSVSEDFL SSVDEENKAD EAKPKSKLPV KVPLQRVEQQ
LSDLDTSVQK TVAPQGQDMA SIAPDNRSKS ESDASSLDSK TKCPVKTRSY TETETESRER
AEELELESEE GATRPKILTS RLPVKSRSTT SSCRGGTSPT KESKEHFFDL YRNSIEFFEE
ISDEASKLVD RLTQSEREQE IVSDDESSSA LEVSVIENLP PVETEHSVPE DIFDTRPIWD
ESIETLIERI PDENGHDHAE DPQDEQERIE ERLAYIADHL GFSWTELARE LDFTEEQIHQ
IRIENPNSLQ DQSHALLKYW LERDGKHATD TNLVECLTKI NRMDIVHLME TNTEPLQERI
SHSYAEIEQT ITLDHSEGFS VLQEELCTAQ HKQKEEQAVS KESETCDHPP IVSEEDISVG
YSTFQDGVPK TEGDSSATAL FPQTHKEQVQ QDFSGKMQDL PEESSLEYQQ EYFVTTPGTE
TSETQKAMIV PSSPSKTPEE VSTPAEEEKL YLQTPTSSER GGSPIIQEPE EPSEHREESS
PRKTSLVIVE SADNQPETCE RLDEDAAFEK GDDMPEIPPE TVTEEEYIDE HGHTVVKKVT
RKIIRRYVSS EGTEKEEIMV QGMPQEPVNI EEGDGYSKVI KRVVLKSDTE QSEDNNE
//
MIM
106410
*RECORD*
*FIELD* NO
106410
*FIELD* TI
*106410 ANKYRIN 2; ANK2
;;ANKYRIN, NONERYTHROID;;
ANKYRIN, BRAIN;;
ANKYRIN, NEURONAL;;
read moreANKYRIN-B
*FIELD* TX
CLONING
Tse et al. (1991) studied immunoreactive isoforms of erythrocyte ankyrin
found in nonerythroid tissues. Using an erythrocyte ankyrin cDNA clone
as a hybridization probe, they isolated a clone from a human genomic
library that hybridized at low but not at high stringency. Further
studies suggested that the clone represented part of a gene for
nonerythroid ankyrin, which they designated ANK2.
Otto et al. (1991) isolated and sequenced cDNAs related to 2 brain
ankyrin isoforms and showed that they are produced through alternative
splicing of the mRNA from a single gene.
GENE STRUCTURE
The ANK2 gene contains 46 exons (Mohler et al., 2007). Exon 38 is
brain-specific.
GENE FUNCTION
The axon initial segment (AIS) is the site at which neural signals
arise, and should be the most efficient site to regulate neural
activity. Kuba et al. (2010) reported that deprivation of auditory input
in an avian brainstem auditory neuron leads to an increase in AIS
length, thus augmenting the excitability of the neuron. The length of
the AIS, defined by the distribution of voltage-gated sodium channels
and the AIS anchoring protein, ankyrin G, increased by 1.7 times in 7
days after auditory input deprivation. This was accompanied by an
increase in the whole-cell sodium current, membrane excitability, and
spontaneous firing. Kuba et al. (2010) concluded that their work
demonstrated homeostatic regulations of the AIS, which may contribute to
the maintenance of the auditory pathway after hearing loss. Furthermore,
plasticity at the spike initiation site suggests a powerful pathway for
refining neuronal computation in the face of strong sensory deprivation.
MAPPING
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization, Tse et al. (1991) assigned the ANK2 gene to 4q25-q27.
By analysis of human/rodent cell hybrids, Otto et al. (1991) assigned
the brain ankyrin gene to chromosome 4.
MOLECULAR GENETICS
Schott et al. (1995) characterized a large French kindred with long QT
syndrome associated with sinus node dysfunction and episodes of atrial
fibrillation segregating as an autosomal dominant trait. They mapped the
disorder to an 18-cM interval on 4q25-q27 (LQT4; 600919). Mohler et al.
(2003) sequenced the ANK2 gene, which maps to the same region, and
identified a glu1425-to-gly (E1425G) missense mutation (106410.0001).
Ankyrin-B appears to be the first identified protein to be implicated in
a congenital long QT syndrome that is not an ion channel or channel
subunit.
Mohler et al. (2004) identified 8 unrelated probands harboring 5
different ankyrin-B loss-of-function mutations
(106410.0001-106410.0005), 4 of which were previously undescribed, and
expanded the phenotype previously described by Schott et al. (1995).
Mohler et al. (2004) found that humans with ankyrin-B mutations display
varying degrees of cardiac dysfunction, including bradycardia, sinus
arrhythmia, idiopathic ventricular fibrillation, catecholaminergic
polymorphic ventricular tachycardia, and risk of sudden death. However,
a prolonged rate-corrected QT interval was not a consistent feature,
indicating that ankyrin-B dysfunction represents a clinical entity
distinct from classic long QT syndromes. The mutations were localized in
the ankyrin-B regulatory domain, which distinguishes function of
ankyrin-B from ankyrin-G (ANK3; 600465) in cardiomyocytes. All mutations
abolished ability of ankyrin-B to restore abnormal Ca(2+) dynamics and
abnormal localization and expression of Na/Ca exchanger, Na/K ATPase,
and InsP3 receptor in ankyrin-B +/- cardiomyocytes. This study,
considered together with the first description of ankyrin-B mutations
associated with cardiac dysfunction (Mohler et al., 2003), supported a
previously undescribed paradigm for human disease due to abnormal
coordination of multiple functionally related ion channels and
transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP3
receptor.
Mohler et al. (2007) identified 4 previously undescribed ANK2 variants
resulting in cardiac dysfunction. They presented the first description
of differences in cellular phenotypes conferred by specific ANK2
variants, and proposed that the various degrees of ankyrin-B loss of
function contribute to the range of severity of cardiac dysfunction.
They concluded that their data identified ANK2 variants as modulators of
human arrhythmias, provided the first insight into the clinical spectrum
of 'ankyrin-B syndrome,' and reinforced the role of ankyrin-B-dependent
protein interactions in regulating cardiac electrogenesis.
ANIMAL MODEL
Mohler et al. (2003) reported that mice heterozygous for a null mutation
in ankyrin-B were haploinsufficient and displayed arrhythmia similar to
humans. The mutation in ankyrin-B resulted in disruption in the cellular
organization of the sodium pump, the sodium/calcium exchanger, and
inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding proteins),
which reduced the targeting of these proteins to the transverse tubules
as well as reducing overall protein level. Ankyrin-B mutation also led
to altered calcium ion signaling in adult cardiomyocytes that resulted
in extrasystoles, and provided a rationale for the arrhythmia. Thus,
Mohler et al. (2003) identified a novel mechanism for cardiac arrhythmia
due to abnormal coordination of multiple functionally related ion
channels and transporters.
*FIELD* AV
.0001
LONG QT SYNDROME 4
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED, INCLUDED
ANK2, GLU1425GLY
In a large French kindred with autosomal dominant type 4 long QT
syndrome (600919), Mohler et al. (2003) demonstrated that the underlying
defect is a glu1425-to-gly (E1425G) missense mutation in ankyrin-B. The
amino acid substitution was the result of an A-to-G transition at
nucleotide position 4274 in exon 36 of the ANK2 gene.
Further studies reported by Mohler et al. (2004) expanded the phenotype
associated with this mutation (see 600919). In a screening of 664
patients for mutations in the ANK2 gene, a Caucasian female was found to
carry the E1425G mutation. She was clinically unaffected and, in
contrast to previously identified E1425G patients (Mohler et al., 2003),
had a normal QTc of 410 msec with a heart rate of 60 beats per minute.
The proband's 67-year-old mother was a carrier of the E1425G variant
with slightly elevated QTc (430-450 msec) and moderately low heart rate
(63 beats per minute). Three sibs of the proband died young of sudden
death at 25, 17, and 15 years of age. The 25-year-old died while winning
a prize. The 17-year-old died in the shower and had previously
experienced syncopal episodes associated with athletics. The 15-year-old
died getting out of the pool after swimming. The E1425G mutation was not
observed in 550 control individuals. It was the only SSCP variant
identified within the ankyrin-B spectrin-binding domain (exons 24-36).
.0002
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, THR1626ASN
In 2 unrelated Caucasian probands from the United States with marginally
elevated QTc and arrhythmia (600919), Mohler et al. (2004) identified a
4877C-A transversion in exon 42 of the ANK2 gene, resulting in a
thr1626-to-asn (T1626N) substitution. One proband was a 46-year-old
female who had a QTc of 450 msec and had experienced syncope, but had a
normal resting heart rate of 72 beats per minute. Her daughter was also
heterozygous for the T1626N mutation and died of sudden death at age 19
years with no previous cardiac symptoms; QTc and heart rate data were
not available. Two sibs, 2 sons, and the mother of the proband were also
carriers of the mutation and had resting QTc in the normal range. At the
time of report, these carriers were asymptomatic. The second proband was
a 51-year-old male who displayed mildly elevated QTc (450 msec) with
sinus arrhythmia (heart rate varying from 50 to 110 beats per minute).
Two of his sibs with normal QTc were heterozygous for the T1626N
mutation but asymptomatic at the time of report. The T1626N mutation was
not observed in 550 control individuals.
.0003
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, LEU1622ILE
In a European Caucasian female with ventricular tachycardia and
ventricular fibrillation (600919), Mohler et al. (2004) identified a
4864C-A transversion in exon 42 of the ANK2 gene, resulting in a
leu1622-to-ile (L1622I) substitution. The proband had a normal QTc and a
resting heart rate of 63 beats per minute. The proband's mother, sister,
and brother were carriers of the mutation, but at the time of report all
had been asymptomatic with normal resting QTc and normal heart rates.
The L1622I mutation was not observed in control individuals.
.0004
LONG QT SYNDROME 4
ANK2, ARG1788TRP
In 2 unrelated probands with long QT syndrome (LQT4; 600919), Mohler et
al. (2004) identified a 5336C-T transition in exon 45 of the ANK2 gene,
resulting in an arg1788-to-trp (R1788W) substitution. One proband was a
37-year-old Caucasian female from the United States. She presented with
syncope (originally treated as a seizure) at age 12 years. This woman
subsequently had multiple episodes of syncope associated with sleep, and
torsades de pointes ventricular tachycardia was documented. Beta-blocker
therapy failed to eliminate symptoms and she was treated with an
implantable cardiac defibrillator. ECGs revealed a heart rate of 60
beats per minute, prominent T-U waves, and prolongation of the QT
interval with a QTc of 530 msec. The proband's son had also been
diagnosed with long QT syndrome. The second proband, heterozygous for
the R1788W mutation, was a Caucasian female from Europe with multiple
episodes of exercise-associated syncope. She presented with
supraventricular and ventricular tachycardias that were reproducibly
elicited by exercise tests. The patient had normal QTc at rest (430
msec), but prolongation of 470 msec was observed after a syncopal
episode. The woman was successfully treated with beta blockers; however,
exercise-induced nonsustained supraventricular and ventricular
arrhythmias persisted. The father of the proband carried the mutation
with QTc of 430 msec and a heart rate of 67 beats per minute. The R1788W
mutation was not identified in 280 DNA samples obtained from individuals
with normal ECG.
.0005
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, GLU1813LYS
In 2 unrelated probands with cardiac arrhythmia and ventricular
fibrillation, respectively (600919), Mohler et al. (2004) identified a
5437G-A transition in exon 45 of the ANK2 gene, resulting in a
glu1813-to-lys (E1813K) substitution. One proband was a 24-year-old
Caucasian female from Europe diagnosed with recurring arrhythmia and
documented torsades de pointes ventricular tachycardia. She presented
with an elevated resting QTc of 490 msec and mild brachycardia (62 beats
per minute). The second proband was a 60-year-old Caucasian male from
the United States who displayed idiopathic ventricular fibrillation
(Priori et al., 2001) with a normal QTc (395 msec), a normal resting
ECG, and a heart rate of 64 beats per minute. The E1813K mutation was
found in 5 DNA samples obtained from individuals with normal ECGs.
*FIELD* RF
1. Kuba, H.; Oichi, Y.; Ohmori, H.: Presynaptic activity regulates
Na+ channel distribution at the axon initial segment. Nature 465:
1075-1078, 2010.
2. Mohler, P. J.; Le Scouarnec, S.; Denjoy, I.; Loew, J. S.; Guicheney,
P.; Caron, L.; Driskell, I. M.; Schott, J.-J.; Norris, K.; Leenhardt,
A.; Kim, R. B.; Escande, D.; Roden, D. M.: Defining the cellular
phenotype of 'ankyrin-B syndrome' variants. Circulation 115: 432-441,
2007.
3. Mohler, P. J.; Schott, J.-J.; Gramolini, A. O.; Dilly, K. W.; Guatimosim,
S.; duBell, W. H.; Song, L.-S.; Haurogne, K.; Kyndt, F.; Ali, M. E.;
Rogers, T. B.; Lederer, W. J.; Escande, D.; Le Marec, H.; Bennett,
V.: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
sudden cardiac death. Nature 421: 634-639, 2003.
4. Mohler, P. J.; Splawski, I.; Napolitano, C.; Bottelli, G.; Sharpe,
L.; Timothy, K.; Priori, S. G.; Keating, M. T.; Bennett, V.: A cardiac
arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat.
Acad. Sci. 101: 9137-9142, 2004.
5. Otto, E.; Kunimoto, M.; McLaughlin, T.; Bennett, V.: Isolation
and characterization of cDNAs encoding human brain ankyrins reveal
a family of alternatively spliced genes. J. Cell Biol. 114: 241-253,
1991.
6. Priori, S. G.; Napolitano, C.; Grillo, M.: Concealed arrhythmogenic
syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc.
Res. 50: 218-223, 2001.
7. Schott, J.-J.; Charpentier, F.; Peltier, S.; Foley, P.; Drouin,
E.; Bouhour, J.-B.; Donnelly, P.; Vergnaud, G.; Bachner, L.; Moisan,
J.-P.; Le Marec, H.; Pascal, O.: Mapping of a gene for long QT syndrome
to chromosome 4q25-27. Am. J. Hum. Genet. 57: 1114-1122, 1995.
8. Tse, W. T.; Menninger, J. C.; Yang-Feng, T. L.; Francke, U.; Sahr,
K. E.; Lux, S. E.; Ward, D. C.; Forget, B. G.: Isolation and chromosomal
localization of a novel non-erythroid ankyrin gene. Genomics 10:
858-866, 1991.
*FIELD* CN
Ada Hamosh - updated: 8/17/2010
Anne M. Stumpf - updated: 10/4/2007
Victor A. McKusick - updated: 8/12/2004
Victor A. McKusick - updated: 7/13/2004
Victor A. McKusick - updated: 2/5/2003
*FIELD* CD
Victor A. McKusick: 5/15/1991
*FIELD* ED
alopez: 08/20/2010
terry: 8/17/2010
alopez: 10/4/2007
carol: 9/3/2004
terry: 8/12/2004
carol: 7/21/2004
carol: 7/15/2004
tkritzer: 7/15/2004
terry: 7/13/2004
alopez: 2/26/2003
alopez: 2/5/2003
terry: 2/5/2003
psherman: 4/3/2000
dkim: 7/17/1998
mark: 3/20/1995
carol: 4/7/1993
carol: 10/23/1992
supermim: 3/16/1992
carol: 8/8/1991
carol: 5/15/1991
*RECORD*
*FIELD* NO
106410
*FIELD* TI
*106410 ANKYRIN 2; ANK2
;;ANKYRIN, NONERYTHROID;;
ANKYRIN, BRAIN;;
ANKYRIN, NEURONAL;;
read moreANKYRIN-B
*FIELD* TX
CLONING
Tse et al. (1991) studied immunoreactive isoforms of erythrocyte ankyrin
found in nonerythroid tissues. Using an erythrocyte ankyrin cDNA clone
as a hybridization probe, they isolated a clone from a human genomic
library that hybridized at low but not at high stringency. Further
studies suggested that the clone represented part of a gene for
nonerythroid ankyrin, which they designated ANK2.
Otto et al. (1991) isolated and sequenced cDNAs related to 2 brain
ankyrin isoforms and showed that they are produced through alternative
splicing of the mRNA from a single gene.
GENE STRUCTURE
The ANK2 gene contains 46 exons (Mohler et al., 2007). Exon 38 is
brain-specific.
GENE FUNCTION
The axon initial segment (AIS) is the site at which neural signals
arise, and should be the most efficient site to regulate neural
activity. Kuba et al. (2010) reported that deprivation of auditory input
in an avian brainstem auditory neuron leads to an increase in AIS
length, thus augmenting the excitability of the neuron. The length of
the AIS, defined by the distribution of voltage-gated sodium channels
and the AIS anchoring protein, ankyrin G, increased by 1.7 times in 7
days after auditory input deprivation. This was accompanied by an
increase in the whole-cell sodium current, membrane excitability, and
spontaneous firing. Kuba et al. (2010) concluded that their work
demonstrated homeostatic regulations of the AIS, which may contribute to
the maintenance of the auditory pathway after hearing loss. Furthermore,
plasticity at the spike initiation site suggests a powerful pathway for
refining neuronal computation in the face of strong sensory deprivation.
MAPPING
By analysis of somatic cell hybrids and by fluorescence in situ
hybridization, Tse et al. (1991) assigned the ANK2 gene to 4q25-q27.
By analysis of human/rodent cell hybrids, Otto et al. (1991) assigned
the brain ankyrin gene to chromosome 4.
MOLECULAR GENETICS
Schott et al. (1995) characterized a large French kindred with long QT
syndrome associated with sinus node dysfunction and episodes of atrial
fibrillation segregating as an autosomal dominant trait. They mapped the
disorder to an 18-cM interval on 4q25-q27 (LQT4; 600919). Mohler et al.
(2003) sequenced the ANK2 gene, which maps to the same region, and
identified a glu1425-to-gly (E1425G) missense mutation (106410.0001).
Ankyrin-B appears to be the first identified protein to be implicated in
a congenital long QT syndrome that is not an ion channel or channel
subunit.
Mohler et al. (2004) identified 8 unrelated probands harboring 5
different ankyrin-B loss-of-function mutations
(106410.0001-106410.0005), 4 of which were previously undescribed, and
expanded the phenotype previously described by Schott et al. (1995).
Mohler et al. (2004) found that humans with ankyrin-B mutations display
varying degrees of cardiac dysfunction, including bradycardia, sinus
arrhythmia, idiopathic ventricular fibrillation, catecholaminergic
polymorphic ventricular tachycardia, and risk of sudden death. However,
a prolonged rate-corrected QT interval was not a consistent feature,
indicating that ankyrin-B dysfunction represents a clinical entity
distinct from classic long QT syndromes. The mutations were localized in
the ankyrin-B regulatory domain, which distinguishes function of
ankyrin-B from ankyrin-G (ANK3; 600465) in cardiomyocytes. All mutations
abolished ability of ankyrin-B to restore abnormal Ca(2+) dynamics and
abnormal localization and expression of Na/Ca exchanger, Na/K ATPase,
and InsP3 receptor in ankyrin-B +/- cardiomyocytes. This study,
considered together with the first description of ankyrin-B mutations
associated with cardiac dysfunction (Mohler et al., 2003), supported a
previously undescribed paradigm for human disease due to abnormal
coordination of multiple functionally related ion channels and
transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP3
receptor.
Mohler et al. (2007) identified 4 previously undescribed ANK2 variants
resulting in cardiac dysfunction. They presented the first description
of differences in cellular phenotypes conferred by specific ANK2
variants, and proposed that the various degrees of ankyrin-B loss of
function contribute to the range of severity of cardiac dysfunction.
They concluded that their data identified ANK2 variants as modulators of
human arrhythmias, provided the first insight into the clinical spectrum
of 'ankyrin-B syndrome,' and reinforced the role of ankyrin-B-dependent
protein interactions in regulating cardiac electrogenesis.
ANIMAL MODEL
Mohler et al. (2003) reported that mice heterozygous for a null mutation
in ankyrin-B were haploinsufficient and displayed arrhythmia similar to
humans. The mutation in ankyrin-B resulted in disruption in the cellular
organization of the sodium pump, the sodium/calcium exchanger, and
inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding proteins),
which reduced the targeting of these proteins to the transverse tubules
as well as reducing overall protein level. Ankyrin-B mutation also led
to altered calcium ion signaling in adult cardiomyocytes that resulted
in extrasystoles, and provided a rationale for the arrhythmia. Thus,
Mohler et al. (2003) identified a novel mechanism for cardiac arrhythmia
due to abnormal coordination of multiple functionally related ion
channels and transporters.
*FIELD* AV
.0001
LONG QT SYNDROME 4
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED, INCLUDED
ANK2, GLU1425GLY
In a large French kindred with autosomal dominant type 4 long QT
syndrome (600919), Mohler et al. (2003) demonstrated that the underlying
defect is a glu1425-to-gly (E1425G) missense mutation in ankyrin-B. The
amino acid substitution was the result of an A-to-G transition at
nucleotide position 4274 in exon 36 of the ANK2 gene.
Further studies reported by Mohler et al. (2004) expanded the phenotype
associated with this mutation (see 600919). In a screening of 664
patients for mutations in the ANK2 gene, a Caucasian female was found to
carry the E1425G mutation. She was clinically unaffected and, in
contrast to previously identified E1425G patients (Mohler et al., 2003),
had a normal QTc of 410 msec with a heart rate of 60 beats per minute.
The proband's 67-year-old mother was a carrier of the E1425G variant
with slightly elevated QTc (430-450 msec) and moderately low heart rate
(63 beats per minute). Three sibs of the proband died young of sudden
death at 25, 17, and 15 years of age. The 25-year-old died while winning
a prize. The 17-year-old died in the shower and had previously
experienced syncopal episodes associated with athletics. The 15-year-old
died getting out of the pool after swimming. The E1425G mutation was not
observed in 550 control individuals. It was the only SSCP variant
identified within the ankyrin-B spectrin-binding domain (exons 24-36).
.0002
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, THR1626ASN
In 2 unrelated Caucasian probands from the United States with marginally
elevated QTc and arrhythmia (600919), Mohler et al. (2004) identified a
4877C-A transversion in exon 42 of the ANK2 gene, resulting in a
thr1626-to-asn (T1626N) substitution. One proband was a 46-year-old
female who had a QTc of 450 msec and had experienced syncope, but had a
normal resting heart rate of 72 beats per minute. Her daughter was also
heterozygous for the T1626N mutation and died of sudden death at age 19
years with no previous cardiac symptoms; QTc and heart rate data were
not available. Two sibs, 2 sons, and the mother of the proband were also
carriers of the mutation and had resting QTc in the normal range. At the
time of report, these carriers were asymptomatic. The second proband was
a 51-year-old male who displayed mildly elevated QTc (450 msec) with
sinus arrhythmia (heart rate varying from 50 to 110 beats per minute).
Two of his sibs with normal QTc were heterozygous for the T1626N
mutation but asymptomatic at the time of report. The T1626N mutation was
not observed in 550 control individuals.
.0003
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, LEU1622ILE
In a European Caucasian female with ventricular tachycardia and
ventricular fibrillation (600919), Mohler et al. (2004) identified a
4864C-A transversion in exon 42 of the ANK2 gene, resulting in a
leu1622-to-ile (L1622I) substitution. The proband had a normal QTc and a
resting heart rate of 63 beats per minute. The proband's mother, sister,
and brother were carriers of the mutation, but at the time of report all
had been asymptomatic with normal resting QTc and normal heart rates.
The L1622I mutation was not observed in control individuals.
.0004
LONG QT SYNDROME 4
ANK2, ARG1788TRP
In 2 unrelated probands with long QT syndrome (LQT4; 600919), Mohler et
al. (2004) identified a 5336C-T transition in exon 45 of the ANK2 gene,
resulting in an arg1788-to-trp (R1788W) substitution. One proband was a
37-year-old Caucasian female from the United States. She presented with
syncope (originally treated as a seizure) at age 12 years. This woman
subsequently had multiple episodes of syncope associated with sleep, and
torsades de pointes ventricular tachycardia was documented. Beta-blocker
therapy failed to eliminate symptoms and she was treated with an
implantable cardiac defibrillator. ECGs revealed a heart rate of 60
beats per minute, prominent T-U waves, and prolongation of the QT
interval with a QTc of 530 msec. The proband's son had also been
diagnosed with long QT syndrome. The second proband, heterozygous for
the R1788W mutation, was a Caucasian female from Europe with multiple
episodes of exercise-associated syncope. She presented with
supraventricular and ventricular tachycardias that were reproducibly
elicited by exercise tests. The patient had normal QTc at rest (430
msec), but prolongation of 470 msec was observed after a syncopal
episode. The woman was successfully treated with beta blockers; however,
exercise-induced nonsustained supraventricular and ventricular
arrhythmias persisted. The father of the proband carried the mutation
with QTc of 430 msec and a heart rate of 67 beats per minute. The R1788W
mutation was not identified in 280 DNA samples obtained from individuals
with normal ECG.
.0005
CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
ANK2, GLU1813LYS
In 2 unrelated probands with cardiac arrhythmia and ventricular
fibrillation, respectively (600919), Mohler et al. (2004) identified a
5437G-A transition in exon 45 of the ANK2 gene, resulting in a
glu1813-to-lys (E1813K) substitution. One proband was a 24-year-old
Caucasian female from Europe diagnosed with recurring arrhythmia and
documented torsades de pointes ventricular tachycardia. She presented
with an elevated resting QTc of 490 msec and mild brachycardia (62 beats
per minute). The second proband was a 60-year-old Caucasian male from
the United States who displayed idiopathic ventricular fibrillation
(Priori et al., 2001) with a normal QTc (395 msec), a normal resting
ECG, and a heart rate of 64 beats per minute. The E1813K mutation was
found in 5 DNA samples obtained from individuals with normal ECGs.
*FIELD* RF
1. Kuba, H.; Oichi, Y.; Ohmori, H.: Presynaptic activity regulates
Na+ channel distribution at the axon initial segment. Nature 465:
1075-1078, 2010.
2. Mohler, P. J.; Le Scouarnec, S.; Denjoy, I.; Loew, J. S.; Guicheney,
P.; Caron, L.; Driskell, I. M.; Schott, J.-J.; Norris, K.; Leenhardt,
A.; Kim, R. B.; Escande, D.; Roden, D. M.: Defining the cellular
phenotype of 'ankyrin-B syndrome' variants. Circulation 115: 432-441,
2007.
3. Mohler, P. J.; Schott, J.-J.; Gramolini, A. O.; Dilly, K. W.; Guatimosim,
S.; duBell, W. H.; Song, L.-S.; Haurogne, K.; Kyndt, F.; Ali, M. E.;
Rogers, T. B.; Lederer, W. J.; Escande, D.; Le Marec, H.; Bennett,
V.: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
sudden cardiac death. Nature 421: 634-639, 2003.
4. Mohler, P. J.; Splawski, I.; Napolitano, C.; Bottelli, G.; Sharpe,
L.; Timothy, K.; Priori, S. G.; Keating, M. T.; Bennett, V.: A cardiac
arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat.
Acad. Sci. 101: 9137-9142, 2004.
5. Otto, E.; Kunimoto, M.; McLaughlin, T.; Bennett, V.: Isolation
and characterization of cDNAs encoding human brain ankyrins reveal
a family of alternatively spliced genes. J. Cell Biol. 114: 241-253,
1991.
6. Priori, S. G.; Napolitano, C.; Grillo, M.: Concealed arrhythmogenic
syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc.
Res. 50: 218-223, 2001.
7. Schott, J.-J.; Charpentier, F.; Peltier, S.; Foley, P.; Drouin,
E.; Bouhour, J.-B.; Donnelly, P.; Vergnaud, G.; Bachner, L.; Moisan,
J.-P.; Le Marec, H.; Pascal, O.: Mapping of a gene for long QT syndrome
to chromosome 4q25-27. Am. J. Hum. Genet. 57: 1114-1122, 1995.
8. Tse, W. T.; Menninger, J. C.; Yang-Feng, T. L.; Francke, U.; Sahr,
K. E.; Lux, S. E.; Ward, D. C.; Forget, B. G.: Isolation and chromosomal
localization of a novel non-erythroid ankyrin gene. Genomics 10:
858-866, 1991.
*FIELD* CN
Ada Hamosh - updated: 8/17/2010
Anne M. Stumpf - updated: 10/4/2007
Victor A. McKusick - updated: 8/12/2004
Victor A. McKusick - updated: 7/13/2004
Victor A. McKusick - updated: 2/5/2003
*FIELD* CD
Victor A. McKusick: 5/15/1991
*FIELD* ED
alopez: 08/20/2010
terry: 8/17/2010
alopez: 10/4/2007
carol: 9/3/2004
terry: 8/12/2004
carol: 7/21/2004
carol: 7/15/2004
tkritzer: 7/15/2004
terry: 7/13/2004
alopez: 2/26/2003
alopez: 2/5/2003
terry: 2/5/2003
psherman: 4/3/2000
dkim: 7/17/1998
mark: 3/20/1995
carol: 4/7/1993
carol: 10/23/1992
supermim: 3/16/1992
carol: 8/8/1991
carol: 5/15/1991
MIM
600919
*RECORD*
*FIELD* NO
600919
*FIELD* TI
#600919 CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
;;ANKYRIN-B SYNDROME
LONG QT SYNDROME 4, INCLUDED; LQT4, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because a cardiac arrhythmia
syndrome with variable manifestations can be caused by loss-of-function
mutations in the ankyrin-B gene (ANK2; 106410).
Long QT syndrome-4 can also be caused by mutation in the ANK2 gene. For
a general phenotypic description and a discussion of genetic
heterogeneity of long QT syndrome, see 192500.
DESCRIPTION
Loss-of-function mutations in ANK2 can result in a broad spectrum of
clinical cardiac phenotypes. Carriers of some mutations (e.g., E1425G,
106410.0001) display QT interval prolongation, stress- and/or
exercise-induced polymorphic ventricular arrhythmia, syncope, and sudden
cardiac death. Patients with other variants show clinical phenotypes,
sometimes mild, extending beyond LQTS, leading to the label 'ankyrin-B
syndrome.' These phenotypes include bradycardia, sinus arrhythmia,
delayed conduction/conduction block, idiopathic ventricular
fibrillation, and catecholaminergic polymorphic ventricular tachycardia
(Mohler et al., 2007).
CLINICAL FEATURES
- Long QT Syndrome 4
Schott et al. (1995) reported a large French family segregating a form
of long QT syndrome. Among 25 affected members (21 adults and 4
children), the average rate-corrected QT interval was 490 ms (for
adults) and 465 ms (for children) compared with 380 ms and 403 ms in
unaffected individuals. Sinus node bradycardia or junctional escape
rhythm was diagnosed in all patients with LQT4. Episodes of atrial
fibrillation were diagnosed in 12 adult patients but were absent during
childhood. Since the initial description, Mohler et al. (2003) reported
that 8 additional individuals had been born, of whom 4 carried the LQT4
haplotype. Sinus node abnormalities were diagnosed in utero in all
affected members from generation 4.
- Ankyrin-B Syndrome
Mohler et al. (2004) expanded the phenotype of the disorder originally
called LQT4 by Schott et al. (1995). They found that 8 unrelated
patients with loss of ankyrin-B activity displayed varying degrees of
cardiac dysfunction, including bradycardia, sinus arrhythmia, idiopathic
ventricular fibrillation, catecholaminergic polymorphic ventricular
tachycardia, and risk of sudden death. However, a prolonged
rate-corrected QT interval was not a consistent feature, indicating that
ankyrin-B dysfunction represents a clinical entity distinct from classic
long QT syndromes.
MAPPING
In a 65-member family in which the long QT syndrome was associated with
more marked sinus bradycardia than usual, leading to sinus node
dysfunction, Schott et al. (1995) excluded linkage to 3 previously
mapped LQT loci on chromosomes 11 (LQT1; 192500), 7 (LQT2; 613688), and
3 (LQT3; 603830). Positive linkage was obtained for markers located on
4q25-q27, with a maximum lod score of 7.05 for marker D4S402.
MOLECULAR GENETICS
Mohler et al. (2003) sequenced the ankyrin-B gene, which was known to
map to the 4q25-q27 region, and identified an A-to-G transition at
position 4274 in exon 36, resulting in a glu1425-to-gly substitution
(E1425G; 106410.0001), in a patient with long QT syndrome-4.
Mohler et al. (2004) identified 8 unrelated probands harboring 5
different ankyrin-B loss-of-function mutations
(106410.0001-106410.0005), 4 of which were previously undescribed, whose
clinical features distinguished the cardiac phenotype from classic long
QT syndromes. The mutations were localized in the ankyrin-B regulatory
domain, which distinguishes function of ankyrin-B from ankyrin-G (ANK3;
600465) in cardiomyocytes.
Mohler et al. (2007) identified 7 novel nonsynonymous variants in ANK2
in patients with a variety of cardiac phenotypes. Four of these variants
displayed abnormal activity in cardiomyocytes.
NOMENCLATURE
Splawski (2004) suggested the designation 'sick sinus syndrome
associated with bradycardia' for this disorder.
ANIMAL MODEL
Mohler et al. (2003) reported that mice heterozygous for a null mutation
in ankyrin-B were haploinsufficient and displayed arrhythmia similar to
humans. Analysis of ECGs and heart rates of unrestrained animals using
implanted radiotransmitter electrodes revealed significant similarities
in cardiac phenotype between humans with LQT4 and AnkB +/- mice. AnkB
+/- mice displayed bradycardia, heart rate variability, and sudden
cardiac death. The mutation in ankyrin-B resulted in disruption in the
cellular organization of the sodium pump, the sodium/calcium exchanger,
and inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding
proteins), which reduced the targeting of these proteins to the
transverse tubules as well as reducing overall protein level. Ankyrin-B
mutation also led to altered calcium ion signaling in adult
cardiomyocytes that resulted in extrasystoles, and provided a rationale
for the arrhythmia. Thus, Mohler et al. (2003) identified a novel
mechanism for cardiac arrhythmia due to abnormal coordination of
multiple functionally related ion channels and transporters.
GENOTYPE/PHENOTYPE CORRELATIONS
In transfection assays in neonatal mouse cardiomyocytes, Mohler et al.
(2007) found that disease-associated human ANK2 mutations caused a range
of in vitro phenotypes, with those variants demonstrating the most
severe loss of function correlating with the most severe human
phenotype. They identified 3 distinct functional classes of ANK2
loss-of-function variants.
*FIELD* RF
1. Mohler, P. J.; Le Scouarnec, S.; Denjoy, I.; Loew, J. S.; Guicheney,
P.; Caron, L.; Driskell, I. M.; Schott, J.-J.; Norris, K.; Leenhardt,
A.; Kim, R. B.; Escande, D.; Roden, D. M.: Defining the cellular
phenotype of 'ankyrin-B syndrome' variants. Circulation 115: 432-441,
2007.
2. Mohler, P. J.; Schott, J.-J.; Gramolini, A. O.; Dilly, K. W.; Guatimosim,
S.; duBell, W. H.; Song, L.-S.; Haurogne, K.; Kyndt, F.; Ali, M. E.;
Rogers, T. B.; Lederer, W. J.; Escande, D.; Le Marec, H.; Bennett,
V.: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
sudden cardiac death. Nature 421: 634-639, 2003.
3. Mohler, P. J.; Splawski, I.; Napolitano, C.; Bottelli, G.; Sharpe,
L.; Timothy, K.; Priori, S. G.; Keating, M. T.; Bennett, V.: A cardiac
arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat.
Acad. Sci. 101: 9137-9142, 2004.
4. Schott, J.-J.; Charpentier, F.; Peltier, S.; Foley, P.; Drouin,
E.; Bouhour, J.-B.; Donnelly, P.; Vergnaud, G.; Bachner, L.; Moisan,
J.-P.; Le Marec, H.; Pascal, O.: Mapping of a gene for long QT syndrome
to chromosome 4q25-27. Am. J. Hum. Genet. 57: 1114-1122, 1995.
5. Splawski, I.: Personal Communication. Boston, Mass. 7/26/2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolong QT interval on EKG;
Sinus bradycardia;
Sinus nude dysfunction;
Atrial fibrillation;
Syncope;
Sudden cardiac death
MISCELLANEOUS:
Genetic heterogeneity (see LQT1 192500)
MOLECULAR BASIS:
Caused by mutation in the ankyrin 2 gene (ANK2, 106410.0001)
*FIELD* CN
Joanna S. Amberger - updated: 2/27/2003
Kelly A. Przylepa - revised: 7/9/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/13/2011
alopez: 10/4/2007
joanna: 2/27/2003
ckniffin: 2/5/2003
joanna: 7/9/2001
*FIELD* CN
Victor A. McKusick - updated: 8/12/2004
Victor A. McKusick - updated: 7/13/2004
Victor A. McKusick - updated: 2/5/2003
*FIELD* CD
Victor A. McKusick: 11/6/1995
*FIELD* ED
carol: 01/14/2011
carol: 1/13/2011
alopez: 10/4/2007
carol: 9/3/2004
terry: 8/12/2004
carol: 7/21/2004
carol: 7/15/2004
tkritzer: 7/15/2004
terry: 7/13/2004
alopez: 2/26/2003
alopez: 2/5/2003
terry: 2/5/2003
carol: 5/25/1999
carol: 5/12/1999
carol: 5/11/1999
terry: 11/6/1995
*RECORD*
*FIELD* NO
600919
*FIELD* TI
#600919 CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
;;ANKYRIN-B SYNDROME
LONG QT SYNDROME 4, INCLUDED; LQT4, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because a cardiac arrhythmia
syndrome with variable manifestations can be caused by loss-of-function
mutations in the ankyrin-B gene (ANK2; 106410).
Long QT syndrome-4 can also be caused by mutation in the ANK2 gene. For
a general phenotypic description and a discussion of genetic
heterogeneity of long QT syndrome, see 192500.
DESCRIPTION
Loss-of-function mutations in ANK2 can result in a broad spectrum of
clinical cardiac phenotypes. Carriers of some mutations (e.g., E1425G,
106410.0001) display QT interval prolongation, stress- and/or
exercise-induced polymorphic ventricular arrhythmia, syncope, and sudden
cardiac death. Patients with other variants show clinical phenotypes,
sometimes mild, extending beyond LQTS, leading to the label 'ankyrin-B
syndrome.' These phenotypes include bradycardia, sinus arrhythmia,
delayed conduction/conduction block, idiopathic ventricular
fibrillation, and catecholaminergic polymorphic ventricular tachycardia
(Mohler et al., 2007).
CLINICAL FEATURES
- Long QT Syndrome 4
Schott et al. (1995) reported a large French family segregating a form
of long QT syndrome. Among 25 affected members (21 adults and 4
children), the average rate-corrected QT interval was 490 ms (for
adults) and 465 ms (for children) compared with 380 ms and 403 ms in
unaffected individuals. Sinus node bradycardia or junctional escape
rhythm was diagnosed in all patients with LQT4. Episodes of atrial
fibrillation were diagnosed in 12 adult patients but were absent during
childhood. Since the initial description, Mohler et al. (2003) reported
that 8 additional individuals had been born, of whom 4 carried the LQT4
haplotype. Sinus node abnormalities were diagnosed in utero in all
affected members from generation 4.
- Ankyrin-B Syndrome
Mohler et al. (2004) expanded the phenotype of the disorder originally
called LQT4 by Schott et al. (1995). They found that 8 unrelated
patients with loss of ankyrin-B activity displayed varying degrees of
cardiac dysfunction, including bradycardia, sinus arrhythmia, idiopathic
ventricular fibrillation, catecholaminergic polymorphic ventricular
tachycardia, and risk of sudden death. However, a prolonged
rate-corrected QT interval was not a consistent feature, indicating that
ankyrin-B dysfunction represents a clinical entity distinct from classic
long QT syndromes.
MAPPING
In a 65-member family in which the long QT syndrome was associated with
more marked sinus bradycardia than usual, leading to sinus node
dysfunction, Schott et al. (1995) excluded linkage to 3 previously
mapped LQT loci on chromosomes 11 (LQT1; 192500), 7 (LQT2; 613688), and
3 (LQT3; 603830). Positive linkage was obtained for markers located on
4q25-q27, with a maximum lod score of 7.05 for marker D4S402.
MOLECULAR GENETICS
Mohler et al. (2003) sequenced the ankyrin-B gene, which was known to
map to the 4q25-q27 region, and identified an A-to-G transition at
position 4274 in exon 36, resulting in a glu1425-to-gly substitution
(E1425G; 106410.0001), in a patient with long QT syndrome-4.
Mohler et al. (2004) identified 8 unrelated probands harboring 5
different ankyrin-B loss-of-function mutations
(106410.0001-106410.0005), 4 of which were previously undescribed, whose
clinical features distinguished the cardiac phenotype from classic long
QT syndromes. The mutations were localized in the ankyrin-B regulatory
domain, which distinguishes function of ankyrin-B from ankyrin-G (ANK3;
600465) in cardiomyocytes.
Mohler et al. (2007) identified 7 novel nonsynonymous variants in ANK2
in patients with a variety of cardiac phenotypes. Four of these variants
displayed abnormal activity in cardiomyocytes.
NOMENCLATURE
Splawski (2004) suggested the designation 'sick sinus syndrome
associated with bradycardia' for this disorder.
ANIMAL MODEL
Mohler et al. (2003) reported that mice heterozygous for a null mutation
in ankyrin-B were haploinsufficient and displayed arrhythmia similar to
humans. Analysis of ECGs and heart rates of unrestrained animals using
implanted radiotransmitter electrodes revealed significant similarities
in cardiac phenotype between humans with LQT4 and AnkB +/- mice. AnkB
+/- mice displayed bradycardia, heart rate variability, and sudden
cardiac death. The mutation in ankyrin-B resulted in disruption in the
cellular organization of the sodium pump, the sodium/calcium exchanger,
and inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding
proteins), which reduced the targeting of these proteins to the
transverse tubules as well as reducing overall protein level. Ankyrin-B
mutation also led to altered calcium ion signaling in adult
cardiomyocytes that resulted in extrasystoles, and provided a rationale
for the arrhythmia. Thus, Mohler et al. (2003) identified a novel
mechanism for cardiac arrhythmia due to abnormal coordination of
multiple functionally related ion channels and transporters.
GENOTYPE/PHENOTYPE CORRELATIONS
In transfection assays in neonatal mouse cardiomyocytes, Mohler et al.
(2007) found that disease-associated human ANK2 mutations caused a range
of in vitro phenotypes, with those variants demonstrating the most
severe loss of function correlating with the most severe human
phenotype. They identified 3 distinct functional classes of ANK2
loss-of-function variants.
*FIELD* RF
1. Mohler, P. J.; Le Scouarnec, S.; Denjoy, I.; Loew, J. S.; Guicheney,
P.; Caron, L.; Driskell, I. M.; Schott, J.-J.; Norris, K.; Leenhardt,
A.; Kim, R. B.; Escande, D.; Roden, D. M.: Defining the cellular
phenotype of 'ankyrin-B syndrome' variants. Circulation 115: 432-441,
2007.
2. Mohler, P. J.; Schott, J.-J.; Gramolini, A. O.; Dilly, K. W.; Guatimosim,
S.; duBell, W. H.; Song, L.-S.; Haurogne, K.; Kyndt, F.; Ali, M. E.;
Rogers, T. B.; Lederer, W. J.; Escande, D.; Le Marec, H.; Bennett,
V.: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and
sudden cardiac death. Nature 421: 634-639, 2003.
3. Mohler, P. J.; Splawski, I.; Napolitano, C.; Bottelli, G.; Sharpe,
L.; Timothy, K.; Priori, S. G.; Keating, M. T.; Bennett, V.: A cardiac
arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat.
Acad. Sci. 101: 9137-9142, 2004.
4. Schott, J.-J.; Charpentier, F.; Peltier, S.; Foley, P.; Drouin,
E.; Bouhour, J.-B.; Donnelly, P.; Vergnaud, G.; Bachner, L.; Moisan,
J.-P.; Le Marec, H.; Pascal, O.: Mapping of a gene for long QT syndrome
to chromosome 4q25-27. Am. J. Hum. Genet. 57: 1114-1122, 1995.
5. Splawski, I.: Personal Communication. Boston, Mass. 7/26/2004.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Prolong QT interval on EKG;
Sinus bradycardia;
Sinus nude dysfunction;
Atrial fibrillation;
Syncope;
Sudden cardiac death
MISCELLANEOUS:
Genetic heterogeneity (see LQT1 192500)
MOLECULAR BASIS:
Caused by mutation in the ankyrin 2 gene (ANK2, 106410.0001)
*FIELD* CN
Joanna S. Amberger - updated: 2/27/2003
Kelly A. Przylepa - revised: 7/9/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 01/13/2011
alopez: 10/4/2007
joanna: 2/27/2003
ckniffin: 2/5/2003
joanna: 7/9/2001
*FIELD* CN
Victor A. McKusick - updated: 8/12/2004
Victor A. McKusick - updated: 7/13/2004
Victor A. McKusick - updated: 2/5/2003
*FIELD* CD
Victor A. McKusick: 11/6/1995
*FIELD* ED
carol: 01/14/2011
carol: 1/13/2011
alopez: 10/4/2007
carol: 9/3/2004
terry: 8/12/2004
carol: 7/21/2004
carol: 7/15/2004
tkritzer: 7/15/2004
terry: 7/13/2004
alopez: 2/26/2003
alopez: 2/5/2003
terry: 2/5/2003
carol: 5/25/1999
carol: 5/12/1999
carol: 5/11/1999
terry: 11/6/1995