Full text data of ANK1
ANK1
(ANK)
[Confidence: high (present in two of the MS resources)]
Ankyrin-1; ANK-1 (Ankyrin-R; Erythrocyte ankyrin)
Ankyrin-1; ANK-1 (Ankyrin-R; Erythrocyte ankyrin)
hRBCD
IPI00216697
IPI00216697 ankyrin 1 isoform 1 ankyrin 1 isoform 1 membrane n/a n/a n/a n/a n/a 35 n/a n/a n/a n/a 111 89 n/a 61 45 n/a n/a 97 n/a n/a cytoskeleton n/a found at its expected molecular weight found at molecular weight
IPI00216697 ankyrin 1 isoform 1 ankyrin 1 isoform 1 membrane n/a n/a n/a n/a n/a 35 n/a n/a n/a n/a 111 89 n/a 61 45 n/a n/a 97 n/a n/a cytoskeleton n/a found at its expected molecular weight found at molecular weight
Comments
Isoform P16157-5 was detected.
Isoform P16157-5 was detected.
UniProt
P16157
ID ANK1_HUMAN Reviewed; 1881 AA.
AC P16157; A0PJN8; A6NJ23; E5RFL7; O43400; Q13768; Q53ER1; Q59FP2;
read moreAC Q8N604; Q99407;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Ankyrin-1;
DE Short=ANK-1;
DE AltName: Full=Ankyrin-R;
DE AltName: Full=Erythrocyte ankyrin;
GN Name=ANK1; Synonyms=ANK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ER1 AND ER2), PROTEIN SEQUENCE OF
RP 3-30; 733-753; 828-871; 959-1003; 1106-1128; 1149-1168; 1282-1288;
RP 1345-1367; 1383-1427; 1601-1626; 1686-1700 AND 1763-1772, AND VARIANTS
RP ALA-750 AND ILE-1075.
RC TISSUE=Hematopoietic;
RX PubMed=2137557; DOI=10.1038/344036a0;
RA Lux S.E., John K.M., Bennett V.;
RT "Analysis of cDNA for human erythrocyte ankyrin indicates a repeated
RT structure with homology to tissue-differentiation and cell-cycle
RT control proteins.";
RL Nature 344:36-42(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ER1; ER5 AND ER16), AND VARIANTS
RP ILE-1075 AND ILE-1546.
RX PubMed=1689849; DOI=10.1073/pnas.87.5.1730;
RA Lambert S., Yu H., Prchal J.T., Lawler J., Ruff P., Speicher D.,
RA Cheung M.C., Kan Y.W., Palek J.;
RT "cDNA sequence for human erythrocyte ankyrin.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1730-1734(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND VARIANTS
RP LEU-991 AND ILE-1075.
RX PubMed=9235914; DOI=10.1074/jbc.272.31.19220;
RA Gallagher P.G., Tse W.T., Scarpa A.L., Lux S.E., Forget B.G.;
RT "Structure and organization of the human ankyrin-1 gene. Basis for
RT complexity of pre-mRNA processing.";
RL J. Biol. Chem. 272:19220-19228(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MU17; MU18; MU19 AND MU20),
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC TISSUE=Skeletal muscle;
RX PubMed=9430667; DOI=10.1074/jbc.273.3.1339;
RA Gallagher P.G., Forget B.G.;
RT "An alternate promoter directs expression of a truncated, muscle-
RT specific isoform of the human ankyrin 1 gene.";
RL J. Biol. Chem. 273:1339-1348(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BR21), AND VARIANT
RP ILE-1075.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS MU17; 22 AND 23).
RC TISSUE=B-cell, and Skeletal muscle;
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 [9]
RP PROTEIN SEQUENCE OF 5-12; 403-422; 797-814; 862-877 AND 899-912,
RP DOMAINS SPTB AND SLC4A1 BINDING, AND VARIANT ASP-1286.
RX PubMed=2141335;
RA Davis L.H., Bennett V.;
RT "Mapping the binding sites of human erythrocyte ankyrin for the anion
RT exchanger and spectrin.";
RL J. Biol. Chem. 265:10589-10596(1990).
RN [10]
RP PROTEIN SEQUENCE OF 99-110; 129-169 AND 233-248, INTERACTION WITH
RP HIF1AN, AND HYDROXYLATION AT ASN-105; ASN-233; ASN-431; ASN-464;
RP ASN-629; ASN-662; ASP-695; ASN-728 AND ASN-761.
RX PubMed=21177872; DOI=10.1074/jbc.M110.193540;
RA Yang M., Ge W., Chowdhury R., Claridge T.D., Kramer H.B.,
RA Schmierer B., McDonough M.A., Gong L., Kessler B.M., Ratcliffe P.J.,
RA Coleman M.L., Schofield C.J.;
RT "Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin
RT family is catalyzed by factor-inhibiting hypoxia-inducible factor.";
RL J. Biol. Chem. 286:7648-7660(2011).
RN [11]
RP INTERACTION WITH SLC4A1.
RX PubMed=7665627; DOI=10.1074/jbc.270.37.22050;
RA Michaely P., Bennett V.;
RT "The ANK repeats of erythrocyte ankyrin form two distinct but
RT cooperative binding sites for the erythrocyte anion exchanger.";
RL J. Biol. Chem. 270:22050-22057(1995).
RN [12]
RP INTERACTION WITH TTN.
RX PubMed=12444090; DOI=10.1074/jbc.M209012200;
RA Kontrogianni-Konstantopoulos A., Bloch R.J.;
RT "The hydrophilic domain of small ankyrin-1 interacts with the two N-
RT terminal immunoglobulin domains of titin.";
RL J. Biol. Chem. 278:3985-3991(2003).
RN [13]
RP SUBCELLULAR LOCATION, INTERACTION WITH OBSCN, AND MUTAGENESIS OF
RP THR-1824; LYS-1826; ARG-1829 AND LYS-1830.
RX PubMed=12527750; DOI=10.1083/jcb.200208109;
RA Bagnato P., Barone V., Giacomello E., Rossi D., Sorrentino V.;
RT "Binding of an ankyrin-1 isoform to obscurin suggests a molecular link
RT between the sarcoplasmic reticulum and myofibrils in striated
RT muscles.";
RL J. Cell Biol. 160:245-253(2003).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
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 [17]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 402-827, AND FUNCTION OF ANK
RP REPEAT DOMAIN.
RX PubMed=12456646; DOI=10.1093/emboj/cdf651;
RA Michaely P., Tomchick D.R., Machius M., Anderson R.G.;
RT "Crystal structure of a 12 ANK repeat stack from human ankyrinR.";
RL EMBO J. 21:6387-6396(2002).
RN [18]
RP STRUCTURE BY NMR OF 1392-1497.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the DEATH domain of ankyrin-1.";
RL Submitted (APR-2008) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 911-1233, AND DOMAINS ZU5.
RX PubMed=22310050; DOI=10.1016/j.jmb.2012.01.041;
RA Yasunaga M., Ipsaro J.J., Mondragon A.;
RT "Structurally similar but functionally diverse ZU5 domains in human
RT erythrocyte ankyrin.";
RL J. Mol. Biol. 417:336-350(2012).
RN [20]
RP VARIANT SPH1 ILE-463.
RX PubMed=8640229; DOI=10.1038/ng0696-214;
RA Eber S.W., Gonzalez J.M., Lux M.L., Scarpa A.L., Tse W.T.,
RA Dornwell M., Herbers J., Kugler W., Oezcan R., Pekrun A.,
RA Gallagher P.G., Schroeter W., Forget B.G., Lux S.E.;
RT "Ankyrin-1 mutations are a major cause of dominant and recessive
RT hereditary spherocytosis.";
RL Nat. Genet. 13:214-218(1996).
RN [21]
RP VARIANTS SPH1 ARG-276 AND THR-1054.
RX PubMed=11102985;
RX DOI=10.1002/1098-1004(200012)16:6<529::AID-HUMU13>3.0.CO;2-N;
RA Leite R.C.A., Basseres D.S., Ferreira J.S., Alberto F.L., Costa F.F.,
RA Saad S.T.O.;
RT "Low frequency of ankyrin mutations in hereditary spherocytosis:
RT identification of three novel mutations.";
RL Hum. Mutat. 16:529-529(2000).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] HIS-332.
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: Attaches integral membrane proteins to cytoskeletal
CC elements; binds to the erythrocyte membrane protein band 4.2, to
CC Na-K ATPase, to the lymphocyte membrane protein GP85, and to the
CC cytoskeletal proteins fodrin, tubulin, vimentin and desmin.
CC Erythrocyte ankyrins also link spectrin (beta chain) to the
CC cytoplasmic domain of the erythrocytes anion exchange protein;
CC they retain most or all of these binding functions.
CC -!- FUNCTION: Isoform Mu17 together with obscurin in skeletal muscle
CC may provide a molecular link between the sarcoplasmic reticulum
CC and myofibrils.
CC -!- SUBUNIT: Interacts with a number of integral membrane proteins and
CC cytoskeletal proteins. Interacts (via N-terminus) with
CC SPTB/spectrin (beta chain). Interacts (via N-terminus ANK repeats)
CC with SLC4A1/erythrocyte membrane protein band 3 (via cytoplasmic
CC N-terminus). Also interacts with TTN/titin. Isoform Mu17 interacts
CC with OBSCN isoform 3/obscurin. Interacts with HIF1AN.
CC -!- INTERACTION:
CC Q5VST9-3:OBSCN; NbExp=8; IntAct=EBI-941819, EBI-941921;
CC -!- SUBCELLULAR LOCATION: Isoform Er1: Cytoplasm, cytoskeleton.
CC Note=Probably the other erythrocyte (Er) isoforms, are located
CC near the surface of erythrocytic plasma membrane.
CC -!- SUBCELLULAR LOCATION: Isoform Mu17: Membrane. Cytoplasm,
CC myofibril, sarcomere, M line. Note=Colocalizes with OBSCN isoform
CC 3/obscurin at the M line in differentiated skeletal muscle cells.
CC -!- SUBCELLULAR LOCATION: Isoform Mu18: Sarcoplasmic reticulum
CC (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform Mu19: Sarcoplasmic reticulum
CC (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform Mu20: Sarcoplasmic reticulum
CC (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=23;
CC Name=Er1; Synonyms=1, 2.1;
CC IsoId=P16157-1; Sequence=Displayed;
CC Note=Major erythrocyte-specific isoform. Produced by alternative
CC promoter usage;
CC Name=Er2; Synonyms=2, 2.2;
CC IsoId=P16157-4; Sequence=VSP_018442;
CC Note=Predominant form of minor erythrocyte-specific isoforms.
CC Produced by alternative splicing of isoform Er1;
CC Name=Er3; Synonyms=3;
CC IsoId=P16157-5; Sequence=VSP_018449;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er4; Synonyms=4;
CC IsoId=P16157-6; Sequence=VSP_018442, VSP_018449;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er5; Synonyms=5;
CC IsoId=P16157-3; Sequence=VSP_000266;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er6; Synonyms=6;
CC IsoId=P16157-7; Sequence=VSP_018442, VSP_000266;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er7; Synonyms=7;
CC IsoId=P16157-8; Sequence=VSP_018447;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er8; Synonyms=8;
CC IsoId=P16157-9; Sequence=VSP_018442, VSP_018447;
CC Name=Er9; Synonyms=9;
CC IsoId=P16157-10; Sequence=VSP_018445;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er10; Synonyms=10;
CC IsoId=P16157-11; Sequence=VSP_018442, VSP_018445;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er11; Synonyms=11;
CC IsoId=P16157-12; Sequence=VSP_018450;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er12; Synonyms=12;
CC IsoId=P16157-13; Sequence=VSP_018442, VSP_018450;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er13; Synonyms=13;
CC IsoId=P16157-14; Sequence=VSP_018451;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er14; Synonyms=14;
CC IsoId=P16157-15; Sequence=VSP_018442, VSP_018451;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er15; Synonyms=15;
CC IsoId=P16157-16; Sequence=VSP_018448;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er16;
CC IsoId=P16157-2; Sequence=VSP_000264, VSP_000265;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Mu17; Synonyms=ank1.5, muscle-specific 1;
CC IsoId=P16157-17; Sequence=VSP_018440, VSP_018443, VSP_000266;
CC Note=Produced by alternative promoter usage. Ref.4 (AAC01950)
CC sequence is in conflict in position: 63:T->P;
CC Name=Mu18; Synonyms=ank1.6, muscle-specific 2;
CC IsoId=P16157-18; Sequence=VSP_018440, VSP_018443, VSP_018448;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Mu19; Synonyms=muscle-specific 3;
CC IsoId=P16157-19; Sequence=VSP_018440, VSP_018443, VSP_018445;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Mu20; Synonyms=muscle-specific 4;
CC IsoId=P16157-20; Sequence=VSP_018440, VSP_018444, VSP_018446;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Br21;
CC IsoId=P16157-21; Sequence=VSP_018439, VSP_018441, VSP_018449;
CC Note=No experimental confirmation available. Produced by
CC alternative splicing of isoform Er1;
CC Name=22;
CC IsoId=P16157-22; Sequence=VSP_018440, VSP_018443, VSP_045439;
CC Note=Produced by alternative splicing;
CC Name=23;
CC IsoId=P16157-23; Sequence=VSP_018440, VSP_018443;
CC -!- TISSUE SPECIFICITY: Isoform Mu17, isoform Mu18, isoform Mu19 and
CC isoform Mu20 are expressed in skeletal muscle. Isoform Br21 is
CC expressed in brain.
CC -!- DOMAIN: The 55 kDa regulatory domain is involved in regulating
CC binding of SPTB/spectrin (beta chain) and SLC4A1/erythrocyte
CC membrane protein band 3.
CC -!- DOMAIN: The ANK repeat region forms a spiral around a large
CC central cavity and is involved in binding of ion transporters.
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 (By
CC similarity).
CC -!- PTM: Regulated by phosphorylation.
CC -!- PTM: Palmitoylated.
CC -!- PTM: Hydroxylated by HIF1AN at several asparagine and 1 aspartate
CC residue within ANK repeat region. Hydroxylation seems to increase
CC the conformational stability of this region and may also modulate
CC protein-protein interactions mediated by the ANK repeat region.
CC -!- DISEASE: Spherocytosis 1 (SPH1) [MIM:182900]: Spherocytosis is a
CC hematologic disorder leading to chronic hemolytic anemia and
CC characterized by numerous abnormally shaped erythrocytes which are
CC generally spheroidal. SPH1 is characterized by severe hemolytic
CC anemia. Inheritance is autosomal recessive. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 23 ANK repeats.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 2 ZU5 domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB47805.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ankyrin entry;
CC URL="http://en.wikipedia.org/wiki/Ankyrin";
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DR EMBL; X16609; CAA34610.1; -; mRNA.
DR EMBL; X16609; CAA34611.1; -; mRNA.
DR EMBL; M28880; AAA51732.1; -; mRNA.
DR EMBL; U50133; AAB47805.1; ALT_SEQ; Genomic_DNA.
DR EMBL; U50092; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50093; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50094; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50095; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50096; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50097; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50098; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50099; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50100; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50101; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50102; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50103; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50104; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50105; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50106; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50107; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50108; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50109; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50110; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50111; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50112; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50113; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50114; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50115; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50116; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50117; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50118; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50119; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50120; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50121; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50122; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50123; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50124; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50125; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50126; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50127; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50128; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50129; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50130; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50131; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50132; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; AF005213; AAC01950.1; -; mRNA.
DR EMBL; AB209418; BAD92655.1; -; mRNA.
DR EMBL; AK223578; BAD97298.1; -; mRNA.
DR EMBL; AC027702; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC113133; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471080; EAW63243.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63244.1; -; Genomic_DNA.
DR EMBL; BC030957; AAH30957.1; -; mRNA.
DR EMBL; BC117121; AAI17122.1; -; mRNA.
DR EMBL; BC014467; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; A35049; A35049.
DR PIR; S08275; SJHUK.
DR RefSeq; NP_000028.3; NM_000037.3.
DR RefSeq; NP_001135917.1; NM_001142445.1.
DR RefSeq; NP_001135918.1; NM_001142446.1.
DR RefSeq; NP_065208.2; NM_020475.2.
DR RefSeq; NP_065209.2; NM_020476.2.
DR RefSeq; NP_065210.2; NM_020477.2.
DR RefSeq; NP_065211.2; NM_020478.4.
DR RefSeq; NP_065213.2; NM_020480.4.
DR UniGene; Hs.654438; -.
DR UniGene; Hs.667377; -.
DR UniGene; Hs.708861; -.
DR PDB; 1N11; X-ray; 2.70 A; A=402-827.
DR PDB; 2YQF; NMR; -; A=1394-1497.
DR PDB; 2YVI; X-ray; 1.92 A; A=1394-1497.
DR PDB; 3F59; X-ray; 2.00 A; A/B/C/D=911-1068.
DR PDB; 3KBT; X-ray; 2.75 A; C/D=911-1068.
DR PDB; 3KBU; X-ray; 2.75 A; C/D=911-1068.
DR PDB; 3UD1; X-ray; 2.00 A; A/B/C=911-1233.
DR PDB; 3UD2; X-ray; 2.21 A; A/B/C=911-1233.
DR PDBsum; 1N11; -.
DR PDBsum; 2YQF; -.
DR PDBsum; 2YVI; -.
DR PDBsum; 3F59; -.
DR PDBsum; 3KBT; -.
DR PDBsum; 3KBU; -.
DR PDBsum; 3UD1; -.
DR PDBsum; 3UD2; -.
DR ProteinModelPortal; P16157; -.
DR SMR; P16157; 5-812, 911-1497.
DR IntAct; P16157; 1.
DR MINT; MINT-254860; -.
DR STRING; 9606.ENSP00000265709; -.
DR PhosphoSite; P16157; -.
DR DMDM; 116241246; -.
DR PaxDb; P16157; -.
DR PRIDE; P16157; -.
DR DNASU; 286; -.
DR Ensembl; ENST00000265709; ENSP00000265709; ENSG00000029534.
DR Ensembl; ENST00000289734; ENSP00000289734; ENSG00000029534.
DR Ensembl; ENST00000314214; ENSP00000319123; ENSG00000029534.
DR Ensembl; ENST00000347528; ENSP00000339620; ENSG00000029534.
DR Ensembl; ENST00000348036; ENSP00000297744; ENSG00000029534.
DR Ensembl; ENST00000352337; ENSP00000309131; ENSG00000029534.
DR Ensembl; ENST00000379758; ENSP00000369082; ENSG00000029534.
DR Ensembl; ENST00000396942; ENSP00000380147; ENSG00000029534.
DR Ensembl; ENST00000396945; ENSP00000380149; ENSG00000029534.
DR Ensembl; ENST00000457297; ENSP00000403589; ENSG00000029534.
DR Ensembl; ENST00000522543; ENSP00000430368; ENSG00000029534.
DR GeneID; 286; -.
DR KEGG; hsa:286; -.
DR UCSC; uc003xoc.3; human.
DR CTD; 286; -.
DR GeneCards; GC08M041510; -.
DR HGNC; HGNC:492; ANK1.
DR HPA; CAB016057; -.
DR HPA; HPA004842; -.
DR MIM; 182900; phenotype.
DR MIM; 612641; gene.
DR neXtProt; NX_P16157; -.
DR Orphanet; 251066; 8p11.2 deletion syndrome.
DR Orphanet; 822; Hereditary spherocytosis.
DR PharmGKB; PA24798; -.
DR eggNOG; COG0666; -.
DR HOVERGEN; HBG004234; -.
DR KO; K10380; -.
DR OMA; RLCQDYD; -.
DR OrthoDB; EOG7P02H2; -.
DR PhylomeDB; P16157; -.
DR Reactome; REACT_111045; Developmental Biology.
DR EvolutionaryTrace; P16157; -.
DR GeneWiki; ANK1; -.
DR GenomeRNAi; 286; -.
DR NextBio; 1155; -.
DR PMAP-CutDB; P16157; -.
DR PRO; PR:P16157; -.
DR ArrayExpress; P16157; -.
DR Bgee; P16157; -.
DR CleanEx; HS_ANK1; -.
DR Genevestigator; P16157; -.
DR GO; GO:0016323; C:basolateral plasma membrane; NAS:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031430; C:M band; IEA:UniProtKB-SubCell.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0014731; C:spectrin-associated cytoskeleton; IDA:BHF-UCL.
DR GO; GO:0008093; F:cytoskeletal adaptor activity; TAS:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; TAS:UniProtKB.
DR GO; GO:0030507; F:spectrin binding; NAS:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007010; P:cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; IDA:BHF-UCL.
DR GO; GO:0048821; P:erythrocyte development; IEA:Ensembl.
DR GO; GO:0006887; P:exocytosis; NAS:UniProtKB.
DR GO; GO:0045199; P:maintenance of epithelial cell apical/basal polarity; TAS:UniProtKB.
DR GO; GO:0015672; P:monovalent inorganic cation transport; IEA:Ensembl.
DR GO; GO:0006779; P:porphyrin-containing compound biosynthetic process; IEA:Ensembl.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
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; 20.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00791; ZU5; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 23.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00218; ZU5; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF48403; SSF48403; 2.
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 promoter usage; Alternative splicing;
KW ANK repeat; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Elliptocytosis;
KW Hereditary hemolytic anemia; Hydroxylation; Lipoprotein; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Sarcoplasmic reticulum.
FT CHAIN 1 1881 Ankyrin-1.
FT /FTId=PRO_0000066883.
FT REPEAT 44 73 ANK 1.
FT REPEAT 77 106 ANK 2.
FT REPEAT 110 139 ANK 3.
FT REPEAT 143 172 ANK 4.
FT REPEAT 174 201 ANK 5.
FT REPEAT 205 234 ANK 6.
FT REPEAT 238 267 ANK 7.
FT REPEAT 271 300 ANK 8.
FT REPEAT 304 333 ANK 9.
FT REPEAT 337 366 ANK 10.
FT REPEAT 370 399 ANK 11.
FT REPEAT 403 432 ANK 12.
FT REPEAT 436 465 ANK 13.
FT REPEAT 469 498 ANK 14.
FT REPEAT 502 531 ANK 15.
FT REPEAT 535 564 ANK 16.
FT REPEAT 568 597 ANK 17.
FT REPEAT 601 630 ANK 18.
FT REPEAT 634 663 ANK 19.
FT REPEAT 667 696 ANK 20.
FT REPEAT 700 729 ANK 21.
FT REPEAT 733 762 ANK 22.
FT REPEAT 766 795 ANK 23.
FT DOMAIN 911 1066 ZU5 1.
FT DOMAIN 1067 1233 ZU5 2.
FT DOMAIN 1403 1487 Death.
FT REGION 1 827 89 kDa domain.
FT REGION 1234 1362 UPA domain (By similarity).
FT REGION 1383 1881 55 kDa regulatory domain.
FT MOD_RES 105 105 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 233 233 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 431 431 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 464 464 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 629 629 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 662 662 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 695 695 (3S)-3-hydroxyaspartate; by HIF1AN;
FT partial.
FT MOD_RES 728 728 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 761 761 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 856 856 Phosphoserine (By similarity).
FT MOD_RES 961 961 Phosphothreonine (By similarity).
FT MOD_RES 1073 1073 Phosphotyrosine (By similarity).
FT MOD_RES 1392 1392 Phosphoserine (By similarity).
FT VAR_SEQ 1 1725 Missing (in isoform Mu17, isoform Mu18,
FT isoform Mu19, isoform Mu20, isoform 22
FT and isoform 23).
FT /FTId=VSP_018440.
FT VAR_SEQ 1 9 MPYSVGFRE -> MAQAAKQLKKIKDIEAQALQEQKEKEES
FT NRKRRNRSRDRKKK (in isoform Br21).
FT /FTId=VSP_018439.
FT VAR_SEQ 820 820 E -> EGTAHITIM (in isoform Br21).
FT /FTId=VSP_018441.
FT VAR_SEQ 1513 1874 Missing (in isoform Er16).
FT /FTId=VSP_000264.
FT VAR_SEQ 1514 1675 Missing (in isoform Er2, isoform Er4,
FT isoform Er6, isoform Er8, isoform Er10,
FT isoform Er12 and isoform Er14).
FT /FTId=VSP_018442.
FT VAR_SEQ 1726 1798 TQGPHSFQGTSTMTEGLEPGGSQEYEKVLVSVSEHTWTEQP
FT EAESSQADRDRRQQGQEEQVQEAKNTFTQVVQ -> MWTFV
FT TQLLVTLVLLSFFLVSCQNVMHIVRGSLCFVLKHIHQELDK
FT ELGESEGLSDDEETISTRVVRRRVFLK (in isoform
FT Mu17, isoform Mu18, isoform Mu19, isoform
FT 22 and isoform 23).
FT /FTId=VSP_018443.
FT VAR_SEQ 1726 1798 TQGPHSFQGTSTMTEGLEPGGSQEYEKVLVSVSEHTWTEQP
FT EAESSQADRDRRQQGQEEQVQEAKNTFTQVVQ -> MWTFV
FT TQLLVTLVLLSFFLVSCQNVMHIVRGSLCFVLKHIHQ (in
FT isoform Mu20).
FT /FTId=VSP_018444.
FT VAR_SEQ 1799 1881 GNEFQNIPGEQVTEEQFTDEQGNIVTKKIIRKVVRQIDLSS
FT ADAAQEHEEVTVEGPLEDPSELEVDIDYFMKHSKDHTSTPN
FT P -> VELRGSGLQPDLIEGRKGAQIVKRASLKRGKQ (in
FT isoform Mu20).
FT /FTId=VSP_018446.
FT VAR_SEQ 1799 1873 Missing (in isoform Er9, isoform Er10 and
FT isoform Mu19).
FT /FTId=VSP_018445.
FT VAR_SEQ 1826 1872 Missing (in isoform 22).
FT /FTId=VSP_045439.
FT VAR_SEQ 1827 1881 IIRKVVRQIDLSSADAAQEHEEVTVEGPLEDPSELEVDIDY
FT FMKHSKDHTSTPNP -> VELRGSGLQPDLIEGRKGAQIVK
FT RASLKRGKQ (in isoform Er15 and isoform
FT Mu18).
FT /FTId=VSP_018448.
FT VAR_SEQ 1827 1873 Missing (in isoform Er7 and isoform Er8).
FT /FTId=VSP_018447.
FT VAR_SEQ 1849 1873 Missing (in isoform Er3, isoform Er4 and
FT isoform Br21).
FT /FTId=VSP_018449.
FT VAR_SEQ 1850 1881 TVEGPLEDPSELEVDIDYFMKHSKDHTSTPNP -> ELRGS
FT GLQPDLIEGRKGAQIVKRASLKRGKQ (in isoform
FT Er5, isoform Er6 and isoform Mu17).
FT /FTId=VSP_000266.
FT VAR_SEQ 1874 1881 DHTSTPNP -> VELRGSGLQPDLIEGRKGAQIVKRASLKR
FT GKQ (in isoform Er11 and isoform Er12).
FT /FTId=VSP_018450.
FT VAR_SEQ 1874 1881 DHTSTPNP -> VLRRPRPWGTQRHHCCLALPGRLHDTSLH
FT SPLYELSLQSLFSLVGSVSAPPCRSFRSSACVLPVFAICPA
FT FCLCCCLQVELRGSGLQPDLIEGRKGAQIVKRASLKRGKQ
FT (in isoform Er13 and isoform Er14).
FT /FTId=VSP_018451.
FT VAR_SEQ 1875 1875 H -> D (in isoform Er16).
FT /FTId=VSP_000265.
FT VARIANT 21 21 R -> T.
FT /FTId=VAR_000595.
FT VARIANT 276 276 L -> R (in SPH1).
FT /FTId=VAR_054991.
FT VARIANT 332 332 D -> H (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035605.
FT VARIANT 463 463 V -> I (in SPH1).
FT /FTId=VAR_000596.
FT VARIANT 619 619 R -> H (in Brueggen; dbSNP:rs2304877).
FT /FTId=VAR_000597.
FT VARIANT 733 733 L -> I (in dbSNP:rs11778936).
FT /FTId=VAR_028769.
FT VARIANT 750 750 V -> A.
FT /FTId=VAR_000598.
FT VARIANT 832 832 R -> Q (in dbSNP:rs34523608).
FT /FTId=VAR_061012.
FT VARIANT 845 845 D -> E.
FT /FTId=VAR_000599.
FT VARIANT 991 991 V -> L.
FT /FTId=VAR_026411.
FT VARIANT 1054 1054 I -> T (in SPH1).
FT /FTId=VAR_054992.
FT VARIANT 1075 1075 T -> I (in dbSNP:rs35213384).
FT /FTId=VAR_048263.
FT VARIANT 1126 1126 A -> P (in dbSNP:rs504465).
FT /FTId=VAR_028770.
FT VARIANT 1192 1192 T -> P (in dbSNP:rs486770).
FT /FTId=VAR_028771.
FT VARIANT 1286 1286 E -> D.
FT /FTId=VAR_000601.
FT VARIANT 1325 1325 M -> V (in dbSNP:rs10093583).
FT /FTId=VAR_028772.
FT VARIANT 1392 1392 S -> T.
FT /FTId=VAR_000600.
FT VARIANT 1546 1546 V -> I (in dbSNP:rs1060130).
FT /FTId=VAR_028773.
FT VARIANT 1592 1592 D -> N (in Duesseldorf).
FT /FTId=VAR_000602.
FT MUTAGEN 1824 1824 T->P: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1826 1826 K->E: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1829 1829 R->G: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1830 1830 K->E: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT CONFLICT 230 230 A -> S (in Ref. 2; AAA51732).
FT CONFLICT 801 801 K -> L (in Ref. 3; AAB47805).
FT CONFLICT 845 845 D -> R (in Ref. 1; AA sequence).
FT CONFLICT 902 902 I -> T (in Ref. 3; AAB47805).
FT HELIX 407 414
FT HELIX 417 425
FT STRAND 433 435
FT HELIX 440 447
FT HELIX 450 459
FT HELIX 473 480
FT HELIX 483 492
FT HELIX 506 513
FT HELIX 516 524
FT HELIX 539 545
FT HELIX 549 557
FT HELIX 572 578
FT HELIX 582 588
FT HELIX 589 591
FT HELIX 605 611
FT HELIX 615 623
FT HELIX 638 644
FT HELIX 648 655
FT TURN 656 658
FT HELIX 671 678
FT HELIX 681 690
FT HELIX 704 710
FT HELIX 715 722
FT HELIX 737 743
FT HELIX 747 755
FT STRAND 765 767
FT HELIX 770 776
FT HELIX 780 789
FT STRAND 914 919
FT STRAND 924 927
FT TURN 930 932
FT STRAND 935 938
FT STRAND 942 945
FT STRAND 947 954
FT HELIX 956 958
FT STRAND 959 961
FT STRAND 970 973
FT STRAND 975 980
FT STRAND 984 994
FT STRAND 1000 1003
FT STRAND 1006 1015
FT STRAND 1018 1020
FT HELIX 1026 1028
FT HELIX 1029 1033
FT HELIX 1043 1049
FT STRAND 1051 1058
FT STRAND 1061 1067
FT STRAND 1074 1076
FT STRAND 1081 1084
FT STRAND 1092 1095
FT STRAND 1099 1102
FT STRAND 1104 1111
FT HELIX 1115 1122
FT STRAND 1131 1138
FT STRAND 1140 1150
FT HELIX 1153 1157
FT STRAND 1165 1167
FT STRAND 1169 1175
FT STRAND 1195 1197
FT STRAND 1200 1207
FT STRAND 1210 1215
FT HELIX 1219 1221
FT HELIX 1222 1232
FT TURN 1398 1402
FT HELIX 1403 1414
FT HELIX 1415 1417
FT HELIX 1418 1424
FT HELIX 1429 1438
FT HELIX 1443 1458
FT HELIX 1459 1461
FT HELIX 1464 1473
FT HELIX 1477 1483
SQ SEQUENCE 1881 AA; 206265 MW; 49466F6F915019EC CRC64;
MPYSVGFREA DAATSFLRAA RSGNLDKALD HLRNGVDINT CNQNGLNGLH LASKEGHVKM
VVELLHKEII LETTTKKGNT ALHIAALAGQ DEVVRELVNY GANVNAQSQK GFTPLYMAAQ
ENHLEVVKFL LENGANQNVA TEDGFTPLAV ALQQGHENVV AHLINYGTKG KVRLPALHIA
ARNDDTRTAA VLLQNDPNPD VLSKTGFTPL HIAAHYENLN VAQLLLNRGA SVNFTPQNGI
TPLHIASRRG NVIMVRLLLD RGAQIETKTK DELTPLHCAA RNGHVRISEI LLDHGAPIQA
KTKNGLSPIH MAAQGDHLDC VRLLLQYDAE IDDITLDHLT PLHVAAHCGH HRVAKVLLDK
GAKPNSRALN GFTPLHIACK KNHVRVMELL LKTGASIDAV TESGLTPLHV ASFMGHLPIV
KNLLQRGASP NVSNVKVETP LHMAARAGHT EVAKYLLQNK AKVNAKAKDD QTPLHCAARI
GHTNMVKLLL ENNANPNLAT TAGHTPLHIA AREGHVETVL ALLEKEASQA CMTKKGFTPL
HVAAKYGKVR VAELLLERDA HPNAAGKNGL TPLHVAVHHN NLDIVKLLLP RGGSPHSPAW
NGYTPLHIAA KQNQVEVARS LLQYGGSANA ESVQGVTPLH LAAQEGHAEM VALLLSKQAN
GNLGNKSGLT PLHLVAQEGH VPVADVLIKH GVMVDATTRM GYTPLHVASH YGNIKLVKFL
LQHQADVNAK TKLGYSPLHQ AAQQGHTDIV TLLLKNGASP NEVSSDGTTP LAIAKRLGYI
SVTDVLKVVT DETSFVLVSD KHRMSFPETV DEILDVSEDE GEELISFKAE RRDSRDVDEE
KELLDFVPKL DQVVESPAIP RIPCAMPETV VIRSEEQEQA SKEYDEDSLI PSSPATETSD
NISPVASPVH TGFLVSFMVD ARGGSMRGSR HNGLRVVIPP RTCAAPTRIT CRLVKPQKLS
TPPPLAEEEG LASRIIALGP TGAQFLSPVI VEIPHFASHG RGDRELVVLR SENGSVWKEH
RSRYGESYLD QILNGMDEEL GSLEELEKKR VCRIITTDFP LYFVIMSRLC QDYDTIGPEG
GSLKSKLVPL VQATFPENAV TKRVKLALQA QPVPDELVTK LLGNQATFSP IVTVEPRRRK
FHRPIGLRIP LPPSWTDNPR DSGEGDTTSL RLLCSVIGGT DQAQWEDITG TTKLVYANEC
ANFTTNVSAR FWLSDCPRTA EAVNFATLLY KELTAVPYMA KFVIFAKMND PREGRLRCYC
MTDDKVDKTL EQHENFVEVA RSRDIEVLEG MSLFAELSGN LVPVKKAAQQ RSFHFQSFRE
NRLAMPVKVR DSSREPGGSL SFLRKAMKYE DTQHILCHLN ITMPPCAKGS GAEDRRRTPT
PLALRYSILS ESTPGSLSGT EQAEMKMAVI SEHLGLSWAE LARELQFSVE DINRIRVENP
NSLLEQSVAL LNLWVIREGQ NANMENLYTA LQSIDRGEIV NMLEGSGRQS RNLKPDRRHT
DRDYSLSPSQ MNGYSSLQDE LLSPASLGCA LSSPLRADQY WNEVAVLDAI PLAATEHDTM
LEMSDMQVWS AGLTPSLVTA EDSSLECSKA EDSDATGHEW KLEGALSEEP RGPELGSLEL
VEDDTVDSDA TNGLIDLLEQ EEGQRSEEKL PGSKRQDDAT GAGQDSENEV SLVSGHQRGQ
ARITHSPTVS QVTERSQDRL QDWDADGSIV SYLQDAAQGS WQEEVTQGPH SFQGTSTMTE
GLEPGGSQEY EKVLVSVSEH TWTEQPEAES SQADRDRRQQ GQEEQVQEAK NTFTQVVQGN
EFQNIPGEQV TEEQFTDEQG NIVTKKIIRK VVRQIDLSSA DAAQEHEEVT VEGPLEDPSE
LEVDIDYFMK HSKDHTSTPN P
//
ID ANK1_HUMAN Reviewed; 1881 AA.
AC P16157; A0PJN8; A6NJ23; E5RFL7; O43400; Q13768; Q53ER1; Q59FP2;
read moreAC Q8N604; Q99407;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Ankyrin-1;
DE Short=ANK-1;
DE AltName: Full=Ankyrin-R;
DE AltName: Full=Erythrocyte ankyrin;
GN Name=ANK1; Synonyms=ANK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ER1 AND ER2), PROTEIN SEQUENCE OF
RP 3-30; 733-753; 828-871; 959-1003; 1106-1128; 1149-1168; 1282-1288;
RP 1345-1367; 1383-1427; 1601-1626; 1686-1700 AND 1763-1772, AND VARIANTS
RP ALA-750 AND ILE-1075.
RC TISSUE=Hematopoietic;
RX PubMed=2137557; DOI=10.1038/344036a0;
RA Lux S.E., John K.M., Bennett V.;
RT "Analysis of cDNA for human erythrocyte ankyrin indicates a repeated
RT structure with homology to tissue-differentiation and cell-cycle
RT control proteins.";
RL Nature 344:36-42(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ER1; ER5 AND ER16), AND VARIANTS
RP ILE-1075 AND ILE-1546.
RX PubMed=1689849; DOI=10.1073/pnas.87.5.1730;
RA Lambert S., Yu H., Prchal J.T., Lawler J., Ruff P., Speicher D.,
RA Cheung M.C., Kan Y.W., Palek J.;
RT "cDNA sequence for human erythrocyte ankyrin.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1730-1734(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING, AND VARIANTS
RP LEU-991 AND ILE-1075.
RX PubMed=9235914; DOI=10.1074/jbc.272.31.19220;
RA Gallagher P.G., Tse W.T., Scarpa A.L., Lux S.E., Forget B.G.;
RT "Structure and organization of the human ankyrin-1 gene. Basis for
RT complexity of pre-mRNA processing.";
RL J. Biol. Chem. 272:19220-19228(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MU17; MU18; MU19 AND MU20),
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC TISSUE=Skeletal muscle;
RX PubMed=9430667; DOI=10.1074/jbc.273.3.1339;
RA Gallagher P.G., Forget B.G.;
RT "An alternate promoter directs expression of a truncated, muscle-
RT specific isoform of the human ankyrin 1 gene.";
RL J. Biol. Chem. 273:1339-1348(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BR21), AND VARIANT
RP ILE-1075.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS MU17; 22 AND 23).
RC TISSUE=B-cell, and Skeletal muscle;
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 [9]
RP PROTEIN SEQUENCE OF 5-12; 403-422; 797-814; 862-877 AND 899-912,
RP DOMAINS SPTB AND SLC4A1 BINDING, AND VARIANT ASP-1286.
RX PubMed=2141335;
RA Davis L.H., Bennett V.;
RT "Mapping the binding sites of human erythrocyte ankyrin for the anion
RT exchanger and spectrin.";
RL J. Biol. Chem. 265:10589-10596(1990).
RN [10]
RP PROTEIN SEQUENCE OF 99-110; 129-169 AND 233-248, INTERACTION WITH
RP HIF1AN, AND HYDROXYLATION AT ASN-105; ASN-233; ASN-431; ASN-464;
RP ASN-629; ASN-662; ASP-695; ASN-728 AND ASN-761.
RX PubMed=21177872; DOI=10.1074/jbc.M110.193540;
RA Yang M., Ge W., Chowdhury R., Claridge T.D., Kramer H.B.,
RA Schmierer B., McDonough M.A., Gong L., Kessler B.M., Ratcliffe P.J.,
RA Coleman M.L., Schofield C.J.;
RT "Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin
RT family is catalyzed by factor-inhibiting hypoxia-inducible factor.";
RL J. Biol. Chem. 286:7648-7660(2011).
RN [11]
RP INTERACTION WITH SLC4A1.
RX PubMed=7665627; DOI=10.1074/jbc.270.37.22050;
RA Michaely P., Bennett V.;
RT "The ANK repeats of erythrocyte ankyrin form two distinct but
RT cooperative binding sites for the erythrocyte anion exchanger.";
RL J. Biol. Chem. 270:22050-22057(1995).
RN [12]
RP INTERACTION WITH TTN.
RX PubMed=12444090; DOI=10.1074/jbc.M209012200;
RA Kontrogianni-Konstantopoulos A., Bloch R.J.;
RT "The hydrophilic domain of small ankyrin-1 interacts with the two N-
RT terminal immunoglobulin domains of titin.";
RL J. Biol. Chem. 278:3985-3991(2003).
RN [13]
RP SUBCELLULAR LOCATION, INTERACTION WITH OBSCN, AND MUTAGENESIS OF
RP THR-1824; LYS-1826; ARG-1829 AND LYS-1830.
RX PubMed=12527750; DOI=10.1083/jcb.200208109;
RA Bagnato P., Barone V., Giacomello E., Rossi D., Sorrentino V.;
RT "Binding of an ankyrin-1 isoform to obscurin suggests a molecular link
RT between the sarcoplasmic reticulum and myofibrils in striated
RT muscles.";
RL J. Cell Biol. 160:245-253(2003).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
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 [17]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 402-827, AND FUNCTION OF ANK
RP REPEAT DOMAIN.
RX PubMed=12456646; DOI=10.1093/emboj/cdf651;
RA Michaely P., Tomchick D.R., Machius M., Anderson R.G.;
RT "Crystal structure of a 12 ANK repeat stack from human ankyrinR.";
RL EMBO J. 21:6387-6396(2002).
RN [18]
RP STRUCTURE BY NMR OF 1392-1497.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the DEATH domain of ankyrin-1.";
RL Submitted (APR-2008) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 911-1233, AND DOMAINS ZU5.
RX PubMed=22310050; DOI=10.1016/j.jmb.2012.01.041;
RA Yasunaga M., Ipsaro J.J., Mondragon A.;
RT "Structurally similar but functionally diverse ZU5 domains in human
RT erythrocyte ankyrin.";
RL J. Mol. Biol. 417:336-350(2012).
RN [20]
RP VARIANT SPH1 ILE-463.
RX PubMed=8640229; DOI=10.1038/ng0696-214;
RA Eber S.W., Gonzalez J.M., Lux M.L., Scarpa A.L., Tse W.T.,
RA Dornwell M., Herbers J., Kugler W., Oezcan R., Pekrun A.,
RA Gallagher P.G., Schroeter W., Forget B.G., Lux S.E.;
RT "Ankyrin-1 mutations are a major cause of dominant and recessive
RT hereditary spherocytosis.";
RL Nat. Genet. 13:214-218(1996).
RN [21]
RP VARIANTS SPH1 ARG-276 AND THR-1054.
RX PubMed=11102985;
RX DOI=10.1002/1098-1004(200012)16:6<529::AID-HUMU13>3.0.CO;2-N;
RA Leite R.C.A., Basseres D.S., Ferreira J.S., Alberto F.L., Costa F.F.,
RA Saad S.T.O.;
RT "Low frequency of ankyrin mutations in hereditary spherocytosis:
RT identification of three novel mutations.";
RL Hum. Mutat. 16:529-529(2000).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] HIS-332.
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: Attaches integral membrane proteins to cytoskeletal
CC elements; binds to the erythrocyte membrane protein band 4.2, to
CC Na-K ATPase, to the lymphocyte membrane protein GP85, and to the
CC cytoskeletal proteins fodrin, tubulin, vimentin and desmin.
CC Erythrocyte ankyrins also link spectrin (beta chain) to the
CC cytoplasmic domain of the erythrocytes anion exchange protein;
CC they retain most or all of these binding functions.
CC -!- FUNCTION: Isoform Mu17 together with obscurin in skeletal muscle
CC may provide a molecular link between the sarcoplasmic reticulum
CC and myofibrils.
CC -!- SUBUNIT: Interacts with a number of integral membrane proteins and
CC cytoskeletal proteins. Interacts (via N-terminus) with
CC SPTB/spectrin (beta chain). Interacts (via N-terminus ANK repeats)
CC with SLC4A1/erythrocyte membrane protein band 3 (via cytoplasmic
CC N-terminus). Also interacts with TTN/titin. Isoform Mu17 interacts
CC with OBSCN isoform 3/obscurin. Interacts with HIF1AN.
CC -!- INTERACTION:
CC Q5VST9-3:OBSCN; NbExp=8; IntAct=EBI-941819, EBI-941921;
CC -!- SUBCELLULAR LOCATION: Isoform Er1: Cytoplasm, cytoskeleton.
CC Note=Probably the other erythrocyte (Er) isoforms, are located
CC near the surface of erythrocytic plasma membrane.
CC -!- SUBCELLULAR LOCATION: Isoform Mu17: Membrane. Cytoplasm,
CC myofibril, sarcomere, M line. Note=Colocalizes with OBSCN isoform
CC 3/obscurin at the M line in differentiated skeletal muscle cells.
CC -!- SUBCELLULAR LOCATION: Isoform Mu18: Sarcoplasmic reticulum
CC (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform Mu19: Sarcoplasmic reticulum
CC (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform Mu20: Sarcoplasmic reticulum
CC (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=23;
CC Name=Er1; Synonyms=1, 2.1;
CC IsoId=P16157-1; Sequence=Displayed;
CC Note=Major erythrocyte-specific isoform. Produced by alternative
CC promoter usage;
CC Name=Er2; Synonyms=2, 2.2;
CC IsoId=P16157-4; Sequence=VSP_018442;
CC Note=Predominant form of minor erythrocyte-specific isoforms.
CC Produced by alternative splicing of isoform Er1;
CC Name=Er3; Synonyms=3;
CC IsoId=P16157-5; Sequence=VSP_018449;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er4; Synonyms=4;
CC IsoId=P16157-6; Sequence=VSP_018442, VSP_018449;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er5; Synonyms=5;
CC IsoId=P16157-3; Sequence=VSP_000266;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er6; Synonyms=6;
CC IsoId=P16157-7; Sequence=VSP_018442, VSP_000266;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er7; Synonyms=7;
CC IsoId=P16157-8; Sequence=VSP_018447;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er8; Synonyms=8;
CC IsoId=P16157-9; Sequence=VSP_018442, VSP_018447;
CC Name=Er9; Synonyms=9;
CC IsoId=P16157-10; Sequence=VSP_018445;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er10; Synonyms=10;
CC IsoId=P16157-11; Sequence=VSP_018442, VSP_018445;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er11; Synonyms=11;
CC IsoId=P16157-12; Sequence=VSP_018450;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er12; Synonyms=12;
CC IsoId=P16157-13; Sequence=VSP_018442, VSP_018450;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er13; Synonyms=13;
CC IsoId=P16157-14; Sequence=VSP_018451;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er14; Synonyms=14;
CC IsoId=P16157-15; Sequence=VSP_018442, VSP_018451;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er15; Synonyms=15;
CC IsoId=P16157-16; Sequence=VSP_018448;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Er16;
CC IsoId=P16157-2; Sequence=VSP_000264, VSP_000265;
CC Note=Produced by alternative splicing of isoform Er1;
CC Name=Mu17; Synonyms=ank1.5, muscle-specific 1;
CC IsoId=P16157-17; Sequence=VSP_018440, VSP_018443, VSP_000266;
CC Note=Produced by alternative promoter usage. Ref.4 (AAC01950)
CC sequence is in conflict in position: 63:T->P;
CC Name=Mu18; Synonyms=ank1.6, muscle-specific 2;
CC IsoId=P16157-18; Sequence=VSP_018440, VSP_018443, VSP_018448;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Mu19; Synonyms=muscle-specific 3;
CC IsoId=P16157-19; Sequence=VSP_018440, VSP_018443, VSP_018445;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Mu20; Synonyms=muscle-specific 4;
CC IsoId=P16157-20; Sequence=VSP_018440, VSP_018444, VSP_018446;
CC Note=Produced by alternative splicing of isoform Mu17;
CC Name=Br21;
CC IsoId=P16157-21; Sequence=VSP_018439, VSP_018441, VSP_018449;
CC Note=No experimental confirmation available. Produced by
CC alternative splicing of isoform Er1;
CC Name=22;
CC IsoId=P16157-22; Sequence=VSP_018440, VSP_018443, VSP_045439;
CC Note=Produced by alternative splicing;
CC Name=23;
CC IsoId=P16157-23; Sequence=VSP_018440, VSP_018443;
CC -!- TISSUE SPECIFICITY: Isoform Mu17, isoform Mu18, isoform Mu19 and
CC isoform Mu20 are expressed in skeletal muscle. Isoform Br21 is
CC expressed in brain.
CC -!- DOMAIN: The 55 kDa regulatory domain is involved in regulating
CC binding of SPTB/spectrin (beta chain) and SLC4A1/erythrocyte
CC membrane protein band 3.
CC -!- DOMAIN: The ANK repeat region forms a spiral around a large
CC central cavity and is involved in binding of ion transporters.
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 (By
CC similarity).
CC -!- PTM: Regulated by phosphorylation.
CC -!- PTM: Palmitoylated.
CC -!- PTM: Hydroxylated by HIF1AN at several asparagine and 1 aspartate
CC residue within ANK repeat region. Hydroxylation seems to increase
CC the conformational stability of this region and may also modulate
CC protein-protein interactions mediated by the ANK repeat region.
CC -!- DISEASE: Spherocytosis 1 (SPH1) [MIM:182900]: Spherocytosis is a
CC hematologic disorder leading to chronic hemolytic anemia and
CC characterized by numerous abnormally shaped erythrocytes which are
CC generally spheroidal. SPH1 is characterized by severe hemolytic
CC anemia. Inheritance is autosomal recessive. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 23 ANK repeats.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 2 ZU5 domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB47805.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ankyrin entry;
CC URL="http://en.wikipedia.org/wiki/Ankyrin";
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DR EMBL; X16609; CAA34610.1; -; mRNA.
DR EMBL; X16609; CAA34611.1; -; mRNA.
DR EMBL; M28880; AAA51732.1; -; mRNA.
DR EMBL; U50133; AAB47805.1; ALT_SEQ; Genomic_DNA.
DR EMBL; U50092; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50093; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50094; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50095; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50096; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50097; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50098; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50099; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50100; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50101; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50102; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50103; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50104; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50105; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50106; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50107; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50108; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50109; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50110; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50111; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50112; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50113; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50114; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50115; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50116; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50117; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50118; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50119; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50120; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50121; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50122; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50123; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50124; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50125; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50126; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50127; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50128; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50129; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50130; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50131; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; U50132; AAB47805.1; JOINED; Genomic_DNA.
DR EMBL; AF005213; AAC01950.1; -; mRNA.
DR EMBL; AB209418; BAD92655.1; -; mRNA.
DR EMBL; AK223578; BAD97298.1; -; mRNA.
DR EMBL; AC027702; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC113133; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471080; EAW63243.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63244.1; -; Genomic_DNA.
DR EMBL; BC030957; AAH30957.1; -; mRNA.
DR EMBL; BC117121; AAI17122.1; -; mRNA.
DR EMBL; BC014467; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; A35049; A35049.
DR PIR; S08275; SJHUK.
DR RefSeq; NP_000028.3; NM_000037.3.
DR RefSeq; NP_001135917.1; NM_001142445.1.
DR RefSeq; NP_001135918.1; NM_001142446.1.
DR RefSeq; NP_065208.2; NM_020475.2.
DR RefSeq; NP_065209.2; NM_020476.2.
DR RefSeq; NP_065210.2; NM_020477.2.
DR RefSeq; NP_065211.2; NM_020478.4.
DR RefSeq; NP_065213.2; NM_020480.4.
DR UniGene; Hs.654438; -.
DR UniGene; Hs.667377; -.
DR UniGene; Hs.708861; -.
DR PDB; 1N11; X-ray; 2.70 A; A=402-827.
DR PDB; 2YQF; NMR; -; A=1394-1497.
DR PDB; 2YVI; X-ray; 1.92 A; A=1394-1497.
DR PDB; 3F59; X-ray; 2.00 A; A/B/C/D=911-1068.
DR PDB; 3KBT; X-ray; 2.75 A; C/D=911-1068.
DR PDB; 3KBU; X-ray; 2.75 A; C/D=911-1068.
DR PDB; 3UD1; X-ray; 2.00 A; A/B/C=911-1233.
DR PDB; 3UD2; X-ray; 2.21 A; A/B/C=911-1233.
DR PDBsum; 1N11; -.
DR PDBsum; 2YQF; -.
DR PDBsum; 2YVI; -.
DR PDBsum; 3F59; -.
DR PDBsum; 3KBT; -.
DR PDBsum; 3KBU; -.
DR PDBsum; 3UD1; -.
DR PDBsum; 3UD2; -.
DR ProteinModelPortal; P16157; -.
DR SMR; P16157; 5-812, 911-1497.
DR IntAct; P16157; 1.
DR MINT; MINT-254860; -.
DR STRING; 9606.ENSP00000265709; -.
DR PhosphoSite; P16157; -.
DR DMDM; 116241246; -.
DR PaxDb; P16157; -.
DR PRIDE; P16157; -.
DR DNASU; 286; -.
DR Ensembl; ENST00000265709; ENSP00000265709; ENSG00000029534.
DR Ensembl; ENST00000289734; ENSP00000289734; ENSG00000029534.
DR Ensembl; ENST00000314214; ENSP00000319123; ENSG00000029534.
DR Ensembl; ENST00000347528; ENSP00000339620; ENSG00000029534.
DR Ensembl; ENST00000348036; ENSP00000297744; ENSG00000029534.
DR Ensembl; ENST00000352337; ENSP00000309131; ENSG00000029534.
DR Ensembl; ENST00000379758; ENSP00000369082; ENSG00000029534.
DR Ensembl; ENST00000396942; ENSP00000380147; ENSG00000029534.
DR Ensembl; ENST00000396945; ENSP00000380149; ENSG00000029534.
DR Ensembl; ENST00000457297; ENSP00000403589; ENSG00000029534.
DR Ensembl; ENST00000522543; ENSP00000430368; ENSG00000029534.
DR GeneID; 286; -.
DR KEGG; hsa:286; -.
DR UCSC; uc003xoc.3; human.
DR CTD; 286; -.
DR GeneCards; GC08M041510; -.
DR HGNC; HGNC:492; ANK1.
DR HPA; CAB016057; -.
DR HPA; HPA004842; -.
DR MIM; 182900; phenotype.
DR MIM; 612641; gene.
DR neXtProt; NX_P16157; -.
DR Orphanet; 251066; 8p11.2 deletion syndrome.
DR Orphanet; 822; Hereditary spherocytosis.
DR PharmGKB; PA24798; -.
DR eggNOG; COG0666; -.
DR HOVERGEN; HBG004234; -.
DR KO; K10380; -.
DR OMA; RLCQDYD; -.
DR OrthoDB; EOG7P02H2; -.
DR PhylomeDB; P16157; -.
DR Reactome; REACT_111045; Developmental Biology.
DR EvolutionaryTrace; P16157; -.
DR GeneWiki; ANK1; -.
DR GenomeRNAi; 286; -.
DR NextBio; 1155; -.
DR PMAP-CutDB; P16157; -.
DR PRO; PR:P16157; -.
DR ArrayExpress; P16157; -.
DR Bgee; P16157; -.
DR CleanEx; HS_ANK1; -.
DR Genevestigator; P16157; -.
DR GO; GO:0016323; C:basolateral plasma membrane; NAS:UniProtKB.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031430; C:M band; IEA:UniProtKB-SubCell.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0014731; C:spectrin-associated cytoskeleton; IDA:BHF-UCL.
DR GO; GO:0008093; F:cytoskeletal adaptor activity; TAS:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; TAS:UniProtKB.
DR GO; GO:0030507; F:spectrin binding; NAS:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007010; P:cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; IDA:BHF-UCL.
DR GO; GO:0048821; P:erythrocyte development; IEA:Ensembl.
DR GO; GO:0006887; P:exocytosis; NAS:UniProtKB.
DR GO; GO:0045199; P:maintenance of epithelial cell apical/basal polarity; TAS:UniProtKB.
DR GO; GO:0015672; P:monovalent inorganic cation transport; IEA:Ensembl.
DR GO; GO:0006779; P:porphyrin-containing compound biosynthetic process; IEA:Ensembl.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
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; 20.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00791; ZU5; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 23.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00218; ZU5; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF48403; SSF48403; 2.
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 promoter usage; Alternative splicing;
KW ANK repeat; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Elliptocytosis;
KW Hereditary hemolytic anemia; Hydroxylation; Lipoprotein; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Sarcoplasmic reticulum.
FT CHAIN 1 1881 Ankyrin-1.
FT /FTId=PRO_0000066883.
FT REPEAT 44 73 ANK 1.
FT REPEAT 77 106 ANK 2.
FT REPEAT 110 139 ANK 3.
FT REPEAT 143 172 ANK 4.
FT REPEAT 174 201 ANK 5.
FT REPEAT 205 234 ANK 6.
FT REPEAT 238 267 ANK 7.
FT REPEAT 271 300 ANK 8.
FT REPEAT 304 333 ANK 9.
FT REPEAT 337 366 ANK 10.
FT REPEAT 370 399 ANK 11.
FT REPEAT 403 432 ANK 12.
FT REPEAT 436 465 ANK 13.
FT REPEAT 469 498 ANK 14.
FT REPEAT 502 531 ANK 15.
FT REPEAT 535 564 ANK 16.
FT REPEAT 568 597 ANK 17.
FT REPEAT 601 630 ANK 18.
FT REPEAT 634 663 ANK 19.
FT REPEAT 667 696 ANK 20.
FT REPEAT 700 729 ANK 21.
FT REPEAT 733 762 ANK 22.
FT REPEAT 766 795 ANK 23.
FT DOMAIN 911 1066 ZU5 1.
FT DOMAIN 1067 1233 ZU5 2.
FT DOMAIN 1403 1487 Death.
FT REGION 1 827 89 kDa domain.
FT REGION 1234 1362 UPA domain (By similarity).
FT REGION 1383 1881 55 kDa regulatory domain.
FT MOD_RES 105 105 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 233 233 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 431 431 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 464 464 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 629 629 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 662 662 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 695 695 (3S)-3-hydroxyaspartate; by HIF1AN;
FT partial.
FT MOD_RES 728 728 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 761 761 (3S)-3-hydroxyasparagine; by HIF1AN;
FT partial.
FT MOD_RES 856 856 Phosphoserine (By similarity).
FT MOD_RES 961 961 Phosphothreonine (By similarity).
FT MOD_RES 1073 1073 Phosphotyrosine (By similarity).
FT MOD_RES 1392 1392 Phosphoserine (By similarity).
FT VAR_SEQ 1 1725 Missing (in isoform Mu17, isoform Mu18,
FT isoform Mu19, isoform Mu20, isoform 22
FT and isoform 23).
FT /FTId=VSP_018440.
FT VAR_SEQ 1 9 MPYSVGFRE -> MAQAAKQLKKIKDIEAQALQEQKEKEES
FT NRKRRNRSRDRKKK (in isoform Br21).
FT /FTId=VSP_018439.
FT VAR_SEQ 820 820 E -> EGTAHITIM (in isoform Br21).
FT /FTId=VSP_018441.
FT VAR_SEQ 1513 1874 Missing (in isoform Er16).
FT /FTId=VSP_000264.
FT VAR_SEQ 1514 1675 Missing (in isoform Er2, isoform Er4,
FT isoform Er6, isoform Er8, isoform Er10,
FT isoform Er12 and isoform Er14).
FT /FTId=VSP_018442.
FT VAR_SEQ 1726 1798 TQGPHSFQGTSTMTEGLEPGGSQEYEKVLVSVSEHTWTEQP
FT EAESSQADRDRRQQGQEEQVQEAKNTFTQVVQ -> MWTFV
FT TQLLVTLVLLSFFLVSCQNVMHIVRGSLCFVLKHIHQELDK
FT ELGESEGLSDDEETISTRVVRRRVFLK (in isoform
FT Mu17, isoform Mu18, isoform Mu19, isoform
FT 22 and isoform 23).
FT /FTId=VSP_018443.
FT VAR_SEQ 1726 1798 TQGPHSFQGTSTMTEGLEPGGSQEYEKVLVSVSEHTWTEQP
FT EAESSQADRDRRQQGQEEQVQEAKNTFTQVVQ -> MWTFV
FT TQLLVTLVLLSFFLVSCQNVMHIVRGSLCFVLKHIHQ (in
FT isoform Mu20).
FT /FTId=VSP_018444.
FT VAR_SEQ 1799 1881 GNEFQNIPGEQVTEEQFTDEQGNIVTKKIIRKVVRQIDLSS
FT ADAAQEHEEVTVEGPLEDPSELEVDIDYFMKHSKDHTSTPN
FT P -> VELRGSGLQPDLIEGRKGAQIVKRASLKRGKQ (in
FT isoform Mu20).
FT /FTId=VSP_018446.
FT VAR_SEQ 1799 1873 Missing (in isoform Er9, isoform Er10 and
FT isoform Mu19).
FT /FTId=VSP_018445.
FT VAR_SEQ 1826 1872 Missing (in isoform 22).
FT /FTId=VSP_045439.
FT VAR_SEQ 1827 1881 IIRKVVRQIDLSSADAAQEHEEVTVEGPLEDPSELEVDIDY
FT FMKHSKDHTSTPNP -> VELRGSGLQPDLIEGRKGAQIVK
FT RASLKRGKQ (in isoform Er15 and isoform
FT Mu18).
FT /FTId=VSP_018448.
FT VAR_SEQ 1827 1873 Missing (in isoform Er7 and isoform Er8).
FT /FTId=VSP_018447.
FT VAR_SEQ 1849 1873 Missing (in isoform Er3, isoform Er4 and
FT isoform Br21).
FT /FTId=VSP_018449.
FT VAR_SEQ 1850 1881 TVEGPLEDPSELEVDIDYFMKHSKDHTSTPNP -> ELRGS
FT GLQPDLIEGRKGAQIVKRASLKRGKQ (in isoform
FT Er5, isoform Er6 and isoform Mu17).
FT /FTId=VSP_000266.
FT VAR_SEQ 1874 1881 DHTSTPNP -> VELRGSGLQPDLIEGRKGAQIVKRASLKR
FT GKQ (in isoform Er11 and isoform Er12).
FT /FTId=VSP_018450.
FT VAR_SEQ 1874 1881 DHTSTPNP -> VLRRPRPWGTQRHHCCLALPGRLHDTSLH
FT SPLYELSLQSLFSLVGSVSAPPCRSFRSSACVLPVFAICPA
FT FCLCCCLQVELRGSGLQPDLIEGRKGAQIVKRASLKRGKQ
FT (in isoform Er13 and isoform Er14).
FT /FTId=VSP_018451.
FT VAR_SEQ 1875 1875 H -> D (in isoform Er16).
FT /FTId=VSP_000265.
FT VARIANT 21 21 R -> T.
FT /FTId=VAR_000595.
FT VARIANT 276 276 L -> R (in SPH1).
FT /FTId=VAR_054991.
FT VARIANT 332 332 D -> H (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035605.
FT VARIANT 463 463 V -> I (in SPH1).
FT /FTId=VAR_000596.
FT VARIANT 619 619 R -> H (in Brueggen; dbSNP:rs2304877).
FT /FTId=VAR_000597.
FT VARIANT 733 733 L -> I (in dbSNP:rs11778936).
FT /FTId=VAR_028769.
FT VARIANT 750 750 V -> A.
FT /FTId=VAR_000598.
FT VARIANT 832 832 R -> Q (in dbSNP:rs34523608).
FT /FTId=VAR_061012.
FT VARIANT 845 845 D -> E.
FT /FTId=VAR_000599.
FT VARIANT 991 991 V -> L.
FT /FTId=VAR_026411.
FT VARIANT 1054 1054 I -> T (in SPH1).
FT /FTId=VAR_054992.
FT VARIANT 1075 1075 T -> I (in dbSNP:rs35213384).
FT /FTId=VAR_048263.
FT VARIANT 1126 1126 A -> P (in dbSNP:rs504465).
FT /FTId=VAR_028770.
FT VARIANT 1192 1192 T -> P (in dbSNP:rs486770).
FT /FTId=VAR_028771.
FT VARIANT 1286 1286 E -> D.
FT /FTId=VAR_000601.
FT VARIANT 1325 1325 M -> V (in dbSNP:rs10093583).
FT /FTId=VAR_028772.
FT VARIANT 1392 1392 S -> T.
FT /FTId=VAR_000600.
FT VARIANT 1546 1546 V -> I (in dbSNP:rs1060130).
FT /FTId=VAR_028773.
FT VARIANT 1592 1592 D -> N (in Duesseldorf).
FT /FTId=VAR_000602.
FT MUTAGEN 1824 1824 T->P: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1826 1826 K->E: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1829 1829 R->G: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT MUTAGEN 1830 1830 K->E: Abolishes interaction with OBSCN
FT (in isoform Mu17).
FT CONFLICT 230 230 A -> S (in Ref. 2; AAA51732).
FT CONFLICT 801 801 K -> L (in Ref. 3; AAB47805).
FT CONFLICT 845 845 D -> R (in Ref. 1; AA sequence).
FT CONFLICT 902 902 I -> T (in Ref. 3; AAB47805).
FT HELIX 407 414
FT HELIX 417 425
FT STRAND 433 435
FT HELIX 440 447
FT HELIX 450 459
FT HELIX 473 480
FT HELIX 483 492
FT HELIX 506 513
FT HELIX 516 524
FT HELIX 539 545
FT HELIX 549 557
FT HELIX 572 578
FT HELIX 582 588
FT HELIX 589 591
FT HELIX 605 611
FT HELIX 615 623
FT HELIX 638 644
FT HELIX 648 655
FT TURN 656 658
FT HELIX 671 678
FT HELIX 681 690
FT HELIX 704 710
FT HELIX 715 722
FT HELIX 737 743
FT HELIX 747 755
FT STRAND 765 767
FT HELIX 770 776
FT HELIX 780 789
FT STRAND 914 919
FT STRAND 924 927
FT TURN 930 932
FT STRAND 935 938
FT STRAND 942 945
FT STRAND 947 954
FT HELIX 956 958
FT STRAND 959 961
FT STRAND 970 973
FT STRAND 975 980
FT STRAND 984 994
FT STRAND 1000 1003
FT STRAND 1006 1015
FT STRAND 1018 1020
FT HELIX 1026 1028
FT HELIX 1029 1033
FT HELIX 1043 1049
FT STRAND 1051 1058
FT STRAND 1061 1067
FT STRAND 1074 1076
FT STRAND 1081 1084
FT STRAND 1092 1095
FT STRAND 1099 1102
FT STRAND 1104 1111
FT HELIX 1115 1122
FT STRAND 1131 1138
FT STRAND 1140 1150
FT HELIX 1153 1157
FT STRAND 1165 1167
FT STRAND 1169 1175
FT STRAND 1195 1197
FT STRAND 1200 1207
FT STRAND 1210 1215
FT HELIX 1219 1221
FT HELIX 1222 1232
FT TURN 1398 1402
FT HELIX 1403 1414
FT HELIX 1415 1417
FT HELIX 1418 1424
FT HELIX 1429 1438
FT HELIX 1443 1458
FT HELIX 1459 1461
FT HELIX 1464 1473
FT HELIX 1477 1483
SQ SEQUENCE 1881 AA; 206265 MW; 49466F6F915019EC CRC64;
MPYSVGFREA DAATSFLRAA RSGNLDKALD HLRNGVDINT CNQNGLNGLH LASKEGHVKM
VVELLHKEII LETTTKKGNT ALHIAALAGQ DEVVRELVNY GANVNAQSQK GFTPLYMAAQ
ENHLEVVKFL LENGANQNVA TEDGFTPLAV ALQQGHENVV AHLINYGTKG KVRLPALHIA
ARNDDTRTAA VLLQNDPNPD VLSKTGFTPL HIAAHYENLN VAQLLLNRGA SVNFTPQNGI
TPLHIASRRG NVIMVRLLLD RGAQIETKTK DELTPLHCAA RNGHVRISEI LLDHGAPIQA
KTKNGLSPIH MAAQGDHLDC VRLLLQYDAE IDDITLDHLT PLHVAAHCGH HRVAKVLLDK
GAKPNSRALN GFTPLHIACK KNHVRVMELL LKTGASIDAV TESGLTPLHV ASFMGHLPIV
KNLLQRGASP NVSNVKVETP LHMAARAGHT EVAKYLLQNK AKVNAKAKDD QTPLHCAARI
GHTNMVKLLL ENNANPNLAT TAGHTPLHIA AREGHVETVL ALLEKEASQA CMTKKGFTPL
HVAAKYGKVR VAELLLERDA HPNAAGKNGL TPLHVAVHHN NLDIVKLLLP RGGSPHSPAW
NGYTPLHIAA KQNQVEVARS LLQYGGSANA ESVQGVTPLH LAAQEGHAEM VALLLSKQAN
GNLGNKSGLT PLHLVAQEGH VPVADVLIKH GVMVDATTRM GYTPLHVASH YGNIKLVKFL
LQHQADVNAK TKLGYSPLHQ AAQQGHTDIV TLLLKNGASP NEVSSDGTTP LAIAKRLGYI
SVTDVLKVVT DETSFVLVSD KHRMSFPETV DEILDVSEDE GEELISFKAE RRDSRDVDEE
KELLDFVPKL DQVVESPAIP RIPCAMPETV VIRSEEQEQA SKEYDEDSLI PSSPATETSD
NISPVASPVH TGFLVSFMVD ARGGSMRGSR HNGLRVVIPP RTCAAPTRIT CRLVKPQKLS
TPPPLAEEEG LASRIIALGP TGAQFLSPVI VEIPHFASHG RGDRELVVLR SENGSVWKEH
RSRYGESYLD QILNGMDEEL GSLEELEKKR VCRIITTDFP LYFVIMSRLC QDYDTIGPEG
GSLKSKLVPL VQATFPENAV TKRVKLALQA QPVPDELVTK LLGNQATFSP IVTVEPRRRK
FHRPIGLRIP LPPSWTDNPR DSGEGDTTSL RLLCSVIGGT DQAQWEDITG TTKLVYANEC
ANFTTNVSAR FWLSDCPRTA EAVNFATLLY KELTAVPYMA KFVIFAKMND PREGRLRCYC
MTDDKVDKTL EQHENFVEVA RSRDIEVLEG MSLFAELSGN LVPVKKAAQQ RSFHFQSFRE
NRLAMPVKVR DSSREPGGSL SFLRKAMKYE DTQHILCHLN ITMPPCAKGS GAEDRRRTPT
PLALRYSILS ESTPGSLSGT EQAEMKMAVI SEHLGLSWAE LARELQFSVE DINRIRVENP
NSLLEQSVAL LNLWVIREGQ NANMENLYTA LQSIDRGEIV NMLEGSGRQS RNLKPDRRHT
DRDYSLSPSQ MNGYSSLQDE LLSPASLGCA LSSPLRADQY WNEVAVLDAI PLAATEHDTM
LEMSDMQVWS AGLTPSLVTA EDSSLECSKA EDSDATGHEW KLEGALSEEP RGPELGSLEL
VEDDTVDSDA TNGLIDLLEQ EEGQRSEEKL PGSKRQDDAT GAGQDSENEV SLVSGHQRGQ
ARITHSPTVS QVTERSQDRL QDWDADGSIV SYLQDAAQGS WQEEVTQGPH SFQGTSTMTE
GLEPGGSQEY EKVLVSVSEH TWTEQPEAES SQADRDRRQQ GQEEQVQEAK NTFTQVVQGN
EFQNIPGEQV TEEQFTDEQG NIVTKKIIRK VVRQIDLSSA DAAQEHEEVT VEGPLEDPSE
LEVDIDYFMK HSKDHTSTPN P
//
MIM
182900
*RECORD*
*FIELD* NO
182900
*FIELD* TI
#182900 SPHEROCYTOSIS, TYPE 1; SPH1
;;SPHEROCYTOSIS, HEREDITARY, 1; HS1;;
SPH; HS
*FIELD* TX
read moreA number sign (#) is used with this entry because spherocytosis type 1
is caused by mutation in the gene encoding ankyrin (ANK1; 612641) on
chromosome 8p11.2.
DESCRIPTION
Hereditary spherocytosis refers to a group of heterogeneous disorders
that are characterized by the presence of spherical-shaped erythrocytes
(spherocytes) on the peripheral blood smear. The disorders are
characterized clinically by anemia, jaundice, and splenomegaly, with
variable severity. Common complications include cholelithiasis,
hemolytic episodes, and aplastic crises (review by Perrotta et al.,
2008).
Elgsaeter et al. (1986) gave an extensive review of the molecular basis
of erythrocyte shape with a discussion of the role of spectrin and other
proteins such as ankyrin, actin (102630), band 4.1 (130500), and band 3
(109270), all of which is relevant to the understanding of spherocytosis
and elliptocytosis (see 611904).
See Delaunay (2007) for a discussion of the molecular basis of
hereditary red cell membrane disorders.
- Genetic Heterogeneity of Hereditary Spherocytosis
Also see spherocytosis type 2 (see 182870), caused by mutation in the
SPTB gene (182870) on chromosome 14q22-q23; spherocytosis type 3
(270970), caused by mutation in the SPTBA gene (182860) on chromosome
1q21; spherocytosis type 4 (see 109270), caused by mutation in the
SLC4A1 gene (109270) on chromosome 17q21-q22; and spherocytosis type 5
(612690), caused by mutation in the EPB42 gene (177070) on chromosome
15q15.
CLINICAL FEATURES
MacKinney et al. (1962) and Morton et al. (1962) studied 26 families.
They concluded that after the initial case in a family has been
identified, 4 tests suffice for the diagnosis in other family members:
smear, reticulocyte count, hemoglobin, and bilirubin. The fragility test
(increased osmotic fragility characterizes the disease) is unnecessary
after the diagnosis has been made in the proband. It was estimated that
the prevalence is 2.2 per 10,000, that the mutation rate is 0.000022 and
that about one-fourth of cases are sporadic. No evidence of reproductive
compensation or of increased prenatal and infant mortality was found. No
enzyme defect was identified (Miwa et al., 1962).
Several observations suggest that more than one type of hereditary
spherocytosis exists in man (review by Zail et al., 1967).
Barry et al. (1968) pointed out that hemochromatosis is a serious
complication of untreated spherocytosis. Fargion et al. (1986) described
2 brothers who were thought to be heterozygous for the hemochromatosis
gene and who also were affected with hereditary spherocytosis. Both had
severe iron overload whereas all relatives without hereditary
spherocytosis, including those with HLA haplotypes identical to those of
the 2 brothers, had normal iron stores. Montes-Cano et al. (2003)
reported a similar situation in a Spanish family: 3 members of different
generations were diagnosed with hereditary spherocytosis and 1 of them,
44 years of age, presented iron overload with hepatic deposit and
required treatment with periodic phlebotomies. Other members of the
family showed normal values in iron metabolism. The patient with iron
overload was a compound heterozygote for the H63D (235200.0002) and
C282Y (235200.0001) mutations in the HFE gene.
In a family with 6 persons affected in 3 generations, Wiley and Firkin
(1970) found a form of hereditary spherocytosis with unusual features;
other reports of atypical disease were reviewed.
Aksoy et al. (1974) described severe hemolytic anemia in a patient
seemingly with both elliptocytosis (inherited probably from the father)
and spherocytosis (inherited from the mother). This finding raises a
question of possible allelism of spherocytosis and one form of
elliptocytosis. A genetic compound is more likely to show summation of
effects than is a double heterozygote.
Epidemic aplastic crisis in congenital chronic hemolytic anemias has
been attributed to the human parvovirus (HPV) which also causes erythema
infectiosum, or fifth disease (Tsukada et al., 1985; Rao et al., 1983).
Lefrere et al. (1986) showed that in both children and adults the human
parvovirus can precipitate aplastic crisis in hereditary spherocytosis
just as it does in other forms of hereditary hemolytic anemia,
particularly sickle cell disease. Healthy persons probably develop an
erythroblastopenia when experiencing their first contact with HPV, but
this escapes notice when the normal red cell life span allows
maintenance of hemoglobin level throughout the interruption of red cell
production. Ng et al. (1987) described a father and a son in whom
aplastic crisis in hereditary spherocytosis was precipitated by
parvovirus infection.
Moiseyev et al. (1987) described a kindred in which hereditary
spherocytosis occurred in combination with hypertrophic cardiomyopathy
in 5 individuals in 4 successive generations. In another branch of the
family, 4 individuals in 3 successive generations had either hereditary
spherocytosis or hypertrophic cardiomyopathy (192600), but not both.
Coetzer et al. (1988) described a 41-year-old man and an unrelated
49-year-old woman who had atypical, severe spherocytosis with partial
response to splenectomy. No information on the family aided in
evaluating inheritance in the second case; in the first case, the
deceased father had had chronic anemia and a sib had died at age 3
months of unknown cause. In these 2 patients, the authors found a
partial deficiency of ankyrin and spectrin in red cells. Coetzer et al.
(1988) concluded that a defect in synthesis of ankyrin was the primary
abnormality.
In the offspring of first-cousin parents, both of whom had hereditary
spherocytosis, Duru et al. (1992) observed a 6-month-old male infant
with severe anemia. The infant required red blood cell transfusions
starting at the age of 1 month and continuing until splenectomy was
performed at the age of 1 year to produce a complete hematologic
remission. Duru et al. (1992) concluded that this represented an example
of homozygosity for the spherocytosis gene, presumably an ankyrin
mutant, and that splenectomy can cure the anemia, even in the
homozygote.
Both sickle cell anemia and hereditary spherocytosis are known causes of
leg ulcers. Peretz et al. (1997) reported the case of an 18-year-old
Bedouin with leg ulcers of 12-months duration; past history revealed HS
since childhood. Treatment for 6 months with various conservative
modalities had no effect on the ulcers. However, complete clearance was
achieved 2 months after splenectomy.
The precocious formation of bilirubinate gallstones is the most common
complication of hereditary spherocytosis, and the prevention of this
problem represents a major impetus for splenectomy in many patients with
compensated hemolysis. Because Gilbert syndrome (143500) had been
considered a risk factor for gallstone formation, Miraglia del Giudice
et al. (1999) postulated that the association of this common inherited
disorder of hepatic bilirubin metabolism with hereditary spherocytosis
could increase cholelithiasis. To test this hypothesis, 103 children
with mild to moderate hereditary spherocytosis who, from age 1 year, had
undergone a liver and biliary tree ultrasonography every year, were
retrospectively examined. The 2-bp TA insertion within the promoter of
the UGT1A1 gene (191740.0011), which is associated with Gilbert
syndrome, was screened. The risk of developing gallstones was
statistically different among the 3 groups of patients (homozygotes for
the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele
with the TA insertion). Miraglia del Giudice et al. (1999) concluded
that although patients with hereditary spherocytosis were the only ones
studied, extrapolating these findings to patients who have different
forms of inherited (e.g., thalassemia, intraerythrocytic enzymatic
deficiency) or acquired (e.g., autoimmune hemolytic anemia, hemolysis
from mechanical heart valve replacement) chronic hemolysis may be
warranted.
- Reviews
Davies and Lux (1989) gave a useful review of hereditary disorders of
the red cell membrane skeleton. They referred to a form of spherocytosis
due to a defect in ankyrin as spherocytosis-1 and a form due to a defect
in beta-spectrin as spherocytosis-2.
Perrotta et al. (2008) reviewed the several forms of hereditary
spherocytosis.
DIAGNOSIS
On behalf of the General Haematology Task Force of the British Committee
for Standards in Haematology, Bolton-Maggs et al. (2004) provided
comprehensive guidelines for the diagnosis and management of hereditary
spherocytosis.
CYTOGENETICS
Kimberling et al. (1975) demonstrated linkage between spherocytosis and
a translocation involving the short arms of chromosomes 8 and 12. They
concluded that the spherocytosis locus is either very close to the
centromere of chromosome 8 or on 12p. Kimberling et al. (1978) reported
further on their studies of a family with HS and an 8-12 translocation.
They concluded that a locus for HS is located near the breakpoint of the
translocation.
Cohen et al. (1991) described 2 sibs in whom congenital spherocytosis
was associated with an inherited interstitial deletion of 8p,
del8(p11-p21). This abnormal chromosome was inherited from their mother
who showed this deletion as well as a small fragment representing the
deleted segment. Centromeric material from chromosome 8 was detected in
this chromosome fragment by in situ hybridization using an
alpha-satellite probe, but not by C banding. Chromosome analysis of skin
fibroblasts from the mother and a third sib, both normal but with a
similar karyotype, showed the deleted fragment in over 80% of cells.
Since the chromosome abnormality was not observed in 5 of the mother's
sibs, it probably arose de novo in her. The 2 sibs with congenital
spherocytosis had multiple other phenotypic abnormalities. The male had
short stature, severe mental retardation, microcephaly, and micrognathia
with bat ears, primary failure of sexual development, and bilateral
conductive deafness secondary to congenital stapedial fixation. In
addition to these features, the sister had torticollis associated with
fusion of several vertebrae; she developed diabetes mellitus at the age
of 15 years, which was controlled by diet and chlorpropamide.
Stratton et al. (1992) described an infant with a de novo interstitial
deletion of the proximal short arm of chromosome 8 (p21p11.2). The
infant had bilateral cleft lip and palate and apparent hypogonadism.
Four previous reports of similar deletions (p21p11.1) were associated
with hypogonadotropic hypogonadism and hereditary spherocytosis. Since
their patient demonstrated no red blood cell abnormality, Stratton et
al. (1992) suggested that the gene for HS is located in the region
8p11.2-p11.1.
Bass et al. (1983) presented evidence for the chromosome 8 localization
of a spherocytosis locus: they observed mother and son with hereditary
spherocytosis and a balanced translocation between chromosomes 3 and 8.
The breakpoint on 8 in the family of Kimberling et al. (1975) and in
their family was at 8p11.
Chilcote et al. (1987) studied 2 dysmorphic sibs with neurologic
findings and hemolytic anemia. Clinical and laboratory findings were
consistent with the diagnosis of congenital spherocytosis whereas both
parents and 2 unaffected sibs were normal. The 2 affected children had
an interstitial deletion of the short arm of chromosome 8,
46,XX,del(8)(p11.1p21.1). Chilcote et al. (1987) suggested that together
with the evidence from the families of Kimberling et al. (1975) and Bass
et al. (1983), their family provides strong evidence for a gene for
congenital spherocytosis in the proximal part of 8p. Glutathione
reductase (GSR; 138300) levels were slightly reduced in the 2 affected
children relative to their parents and an unaffected sib but did not
approach the half-normal values that might be expected and it was
unlikely that the moderate reduction in the glutathione reductase
activity would cause hemolysis. The presence of abnormalities in 2 sibs
with normal parents may have its explanation in mosaicism of 1 parent.
Close linkage to GSR, which is at 8p21, was excluded by the family of
Nakashima et al. (1978).
Kitatani et al. (1988) studied a 1-year-old boy with spherocytosis
associated with a de novo minute deletion involving 8p21.1-p11.22.
Contradictory information on the mapping of hereditary spherocytosis may
reflect genetic heterogeneity in this condition as in elliptocytosis.
Costa et al. (1990) identified reports of 5 cases of deletion or
translocation involving chromosome 8p and leading to spherocytosis.
Lux et al. (1990) reported that 1 copy of the ankyrin gene was missing
from DNA of 2 unrelated children with severe spherocytosis and
heterozygous deletion of chromosome 8--del(8)(p11-p21.1). Affected red
cells were also ankyrin-deficient.
Okamoto et al. (1995) described a 30-month-old Japanese boy with
spherocytic anemia in association with multiple anomalies and mental
retardation. The karyotype had a deletion of interstitial deletion of
8p: del(8)(p11.23p21.1). Glutathione reductase activity was moderately
reduced, consistent with deletion of that locus as well as of the
ankyrin locus. Okamoto et al. (1995) reviewed the other cases of 8p
deletion associated with spherocytic anemia.
PATHOGENESIS
Jacob and Jandl (1964) were of the view that the primary defect is in
the red cell membrane, which is abnormally permeable to sodium.
Jacob et al. (1971) demonstrated altered membrane protein in hereditary
spherocytosis. Microfilamentous proteins resembling actin are important
to the shape of the red cell. Comparable membrane proteins occur
throughout phylogeny under circumstances suggesting a role in cell
plasticity and shape. Actin and myosin-like filamentous proteins occur
in platelets.
Heterogeneity in hereditary spherocytosis was indicated by studies of
structural proteins of the red cell membrane, including alpha and beta
spectrin,. actin (see 102630), and protein 4.1 (EPB41; 130500). In a
systematic assay of the interactions of spectrin in 6 kindreds with
autosomal dominant hereditary spherocytosis, Wolfe et al. (1982) found 1
in which all 4 affected members had reduced enhancement of
spectrin-actin binding by protein 4.1, owing to a 39% decrease in the
binding of normal protein 4.1 by spectrin. The defective spectrin was
separated into 2 populations by affinity chromatography on immobilized
normal protein 4.1. One population lacked ability to bind 4.1, but the
other functioned normally.
Hill et al. (1982) concluded that 'the difference between HS and normal
membranes, which persists in isolated cytoskeletons, suggests that
alterations in either the primary structure or the degree of
phosphorylation of protein bands 2.1 or 4.1 may be central to the
molecular basis of hereditary spherocytosis.' The 2.1 band is also known
as ankyrin. The major proteins of the cytoskeleton, spectrin and actin,
are attached to the cell membrane by bands 2.1 and 4.1. Johnsson and
Himberg (1982) presented evidence that platelets, as well as red cells,
are defective in HS.
In a 41-year old man with severe spherocytosis, Coetzer et al. (1988)
studied the synthesis, assembly, and turnover of spectrin and ankyrin in
the reticulocytes of the first patient. The synthesis of spectrin, when
measured in the cell cytosol, was normal (alpha-spectrin; 182860) or
increased (beta-spectrin; 182870). The principal defect appeared to be a
diminished incorporation of ankyrin into the cell membrane, leading to
decreased deposition of spectrin as a secondary phenomenon. Ankyrin is
the principal binding site for spectrin on the membrane. Normal red
cells contain 1 copy of ankyrin per spectrin tetramer. The red cell
membrane skeleton is a submembranous network composed mainly of
spectrin, actin, and proteins that migrate on gel electrophoresis as
bands 4.1 (EPB41; 130500) and 4.9 (EPB49; 125305). Visualization of the
skeleton by electron microscopy shows a primarily hexagonal lattice of
fibers of spectrin tetramers linked to junctional complexes containing
actin and proteins 4.1 and 4.9. The skeleton is attached to the cell
membrane by ankyrin (protein 2.1), which connects beta-spectrin to the
cytoplasmic portion of band 3 (SLC4A1; 109270), which is the major
integral membrane protein. In addition, protein 4.1 links the distal
ends of spectrin tetramers to transmembrane glycoprotein.
Hanspal et al. (1991) concluded that the primary defect underlying the
combined spectrin and ankyrin deficiency in severe hereditary
spherocytosis is a deficiency of ankyrin mRNA leading to a reduced
synthesis of ankyrin, which, in turn, underlies a decreased assembly of
spectrin on the membrane.
MAPPING
Using RFLPs defined by a cDNA for human erythrocyte ankyrin, Forget et
al. (1989) demonstrated close linkage between hereditary spherocytosis
and the ankyrin gene, with no crossovers observed. The calculated lod
score was 3.63 at a theta of 0.0. The ankyrin gene appears to be located
on the short arm of chromosome 8. The large kindred in which the linkage
was established had classic features.
Costa et al. (1990) analyzed a large kindred with typical dominant
hereditary spherocytosis for genetic linkage with the genes for alpha
spectrin, beta spectrin, protein 4.1, and ankyrin by means of RFLPs.
Close linkage was excluded for all of the candidate genes except that
for ankyrin, which was found to show no recombination, with a lod score
of 3.63.
By fluorescence-based in situ hybridization, Tse et al. (1990) localized
the ankyrin gene to 8p11.2.
MOLECULAR GENETICS
Davies and Lux (1989) stated that dosage analysis in 2 hereditary
spherocytosis patients with chromosome 8p11 deletions showed them to be
hemizygous for the ankyrin gene. A corresponding reduction of
approximately 50% in the amount of ankyrin protein was also seen in
these patients, who had mental retardation in addition to the red cell
defect. In both normoblastosis mice and hereditary spherocytosis humans,
spectrin is also reduced as a secondary phenomenon.
Iolascon et al. (1991) described 2 Italian families with ankyrin
deficiency spherocytosis. In both, the disorder was a new mutation in
the proband; 1 proband transmitted it to an offspring.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime
untranslated/promoter region of ankyrin-1 and the 19 coding exons of
band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They
identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense
mutations and a mutation in the putative ankyrin-1 promoter were common
in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3
frameshift and nonsense null mutations prevailed in dominant HS.
Increased accumulation of the normal protein product partially
compensated for the ankyrin-1 or band 3 defects in some of these null
mutations. The findings indicated to Eber et al. (1996) that ankyrin-1
mutations are a major cause of dominant and recessive HS (between 35 and
65%), that band 3 mutations are less common (between 15 and 25%), and
that the severity of HS is modified by factors other than the primary
gene defect.
Gallagher and Forget (1998) tabulated a total of 34 mutations in the
ANK1 gene that have been associated with hereditary spherocytosis, as
contrasted with 2 mutations in the alpha-spectrin gene and 19 in the
beta-spectrin gene.
In the proband reported by Duru et al. (1992), Edelman et al. (2007)
identified a homozygous splice site mutation in the ANK1 gene
(612641.0007). Each parent was heterozygous for the mutation.
ANIMAL MODEL
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb
locus maps to mouse chromosome 8 in a segment that shows homology of
synteny with human 8p (White and Barker, 1987). White et al. (1990) used
immunologic and biochemical methods to demonstrate an altered (150 kD)
immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+)
reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia,
significant neurologic dysfunction associated with Purkinje cell
degeneration in the cerebellum and the development of a late-onset
neurologic syndrome characterized by persistent tremor and gait
disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin
(HBG1; 142200) reporter gene in an erythroid-specific,
position-independent, copy number-dependent fashion in transgenic mice
to study spherocytosis-associated promoter mutations. They detected
abnormalities in reporter gene mRNA and protein expression. Mice with
the wildtype promoter demonstrated normal expression in all
erythrocytes, whereas mice with the -108T-C promoter mutation
(612641.0002) demonstrated varied expression. Undetectable or
significantly lower expression was found in mice with linked -108T-C and
-153G-A (612641.0006) promoter mutations. Gallagher et al. (2001)
concluded that functional defects can be caused by HS-related ankyrin
gene promoter mutations.
HISTORY
Sengar et al. (1977) presented some fragmentary evidence that HLA and
hereditary spherocytosis may be linked.
De Jongh et al. (1982) could demonstrate no linkage of spherocytosis
with Gm or with HLA. Lod scores with PI were also negative.
*FIELD* SA
Gallagher and Forget (1998); Jacob (1968); Jacob (1966); Jacob
(1965); Jacob et al. (1971); Jandl and Cooper (1972); Jensson et al.
(1977); Kirkpatrick et al. (1975); Lux et al. (1990); MacKinney (1965);
MacPherson et al. (1971); Masera et al. (1980); Mohler and Wheby (1986);
Mohler and Wheby (1984); Motulsky et al. (1962); Nozawa et al. (1974);
Reznikoff-Etievant et al. (1980); Shohet (1979); Wichterle et al.
(1996); Wiley (1972)
*FIELD* RF
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67. White, R. A.; Birkenmeier, C. S.; Lux, S. E.; Barker, J. E.:
Ankyrin and the hemolytic anemia mutation, nb, map to mouse chromosome
8: presence of the nb allele is associated with a truncated erythrocyte
ankyrin. Proc. Nat. Acad. Sci. 87: 3117-3121, 1990.
68. Wichterle, H.; Hanspal, M.; Palek, J.; Jarolim, P.: Combination
of two mutant alpha spectrin alleles underlies a severe spherocytic
hemolytic anemia. J. Clin. Invest. 98: 2300-2307, 1996.
69. Wiley, J. S.: Co-ordinated increase of sodium leak and sodium
pump in hereditary spherocytosis. Brit. J. Haemat. 22: 529-542,
1972.
70. Wiley, J. S.; Firkin, B. G.: An unusual variant of hereditary
spherocytosis. Am. J. Med. 48: 63-71, 1970.
71. Wolfe, L. C.; John, K. M.; Falcone, J. C.; Byrne, A. M.; Lux,
S. E.: A genetic defect in the binding of protein 4.1 to spectrin
in a kindred with hereditary spherocytosis. New Eng. J. Med. 307:
1367-1374, 1982.
72. Zail, S. S.; Krawitz, E.; Viljoen, E.; Kramer, S.; Metz, J.:
Atypical hereditary spherocytosis: biochemical studies and sites of
erythrocyte destruction. Brit. J. Haemat. 13: 323-334, 1967.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Jaundice;
[Biliary tract];
Gallstones;
[Spleen];
Splenomegaly
HEMATOLOGY:
Spherocytosis;
Hemolytic anemia;
Reticulocytosis
LABORATORY ABNORMALITIES:
Increased reticulocyte count;
Hyperbilirubinemia;
Increased osmotic fragility;
Negative direct antiglobulin (Coombs) test;
Elevated MCHC
MISCELLANEOUS:
Autosomal recessive inheritance can occur;
Patients with homozygous mutations have a more severe disorder
MOLECULAR BASIS:
Caused by mutation in the ankyrin 1 gene (ANK1, 182900.0001);
Caused by mutation in the spectrin beta-1 gene (SPTB, 182870.0010);
Caused by mutation in the erythrocytic protein 4.2 gene (EPB42, 177070.0001);
Caused by mutation in the red cell membrane band 3 gene (BND3, 109270.0003)
*FIELD* CN
Cassandra L. Kniffin - updated: 9/17/2007
Kelly A. Przylepa - revised: 9/19/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/24/2011
ckniffin: 9/17/2007
joanna: 5/24/2002
kayiaros: 9/19/2000
*FIELD* CN
Carol A. Bocchini - updated: 2/26/2009
George E. Tiller - updated: 1/23/2009
Cassandra L. Kniffin - updated: 9/17/2007
Victor A. McKusick - updated: 10/20/2004
Victor A. McKusick - updated: 1/23/2004
Paul J. Converse - updated: 1/18/2002
Victor A. McKusick - updated: 4/6/2001
Paul J. Converse - updated: 6/8/2000
Victor A. McKusick - updated: 1/6/2000
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 3/31/1998
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
terry: 04/06/2011
carol: 3/23/2011
terry: 5/4/2009
terry: 3/24/2009
carol: 3/24/2009
carol: 3/18/2009
carol: 3/11/2009
carol: 3/10/2009
terry: 2/26/2009
carol: 2/26/2009
terry: 2/9/2009
wwang: 1/23/2009
carol: 12/8/2008
mgross: 2/21/2008
wwang: 9/24/2007
ckniffin: 9/17/2007
tkritzer: 10/22/2004
terry: 10/20/2004
carol: 3/17/2004
tkritzer: 1/29/2004
terry: 1/23/2004
terry: 11/24/2003
terry: 3/6/2002
mgross: 1/18/2002
mcapotos: 4/11/2001
mcapotos: 4/6/2001
terry: 4/6/2001
carol: 10/20/2000
carol: 6/8/2000
mgross: 1/12/2000
terry: 1/6/2000
terry: 3/1/1999
carol: 2/27/1999
dkim: 9/11/1998
dkim: 7/17/1998
carol: 7/16/1998
terry: 7/13/1998
terry: 6/3/1998
psherman: 3/31/1998
terry: 3/26/1998
alopez: 6/3/1997
mark: 7/22/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 9/14/1995
mimadm: 3/25/1995
davew: 8/1/1994
carol: 2/19/1993
carol: 12/23/1992
carol: 10/23/1992
*RECORD*
*FIELD* NO
182900
*FIELD* TI
#182900 SPHEROCYTOSIS, TYPE 1; SPH1
;;SPHEROCYTOSIS, HEREDITARY, 1; HS1;;
SPH; HS
*FIELD* TX
read moreA number sign (#) is used with this entry because spherocytosis type 1
is caused by mutation in the gene encoding ankyrin (ANK1; 612641) on
chromosome 8p11.2.
DESCRIPTION
Hereditary spherocytosis refers to a group of heterogeneous disorders
that are characterized by the presence of spherical-shaped erythrocytes
(spherocytes) on the peripheral blood smear. The disorders are
characterized clinically by anemia, jaundice, and splenomegaly, with
variable severity. Common complications include cholelithiasis,
hemolytic episodes, and aplastic crises (review by Perrotta et al.,
2008).
Elgsaeter et al. (1986) gave an extensive review of the molecular basis
of erythrocyte shape with a discussion of the role of spectrin and other
proteins such as ankyrin, actin (102630), band 4.1 (130500), and band 3
(109270), all of which is relevant to the understanding of spherocytosis
and elliptocytosis (see 611904).
See Delaunay (2007) for a discussion of the molecular basis of
hereditary red cell membrane disorders.
- Genetic Heterogeneity of Hereditary Spherocytosis
Also see spherocytosis type 2 (see 182870), caused by mutation in the
SPTB gene (182870) on chromosome 14q22-q23; spherocytosis type 3
(270970), caused by mutation in the SPTBA gene (182860) on chromosome
1q21; spherocytosis type 4 (see 109270), caused by mutation in the
SLC4A1 gene (109270) on chromosome 17q21-q22; and spherocytosis type 5
(612690), caused by mutation in the EPB42 gene (177070) on chromosome
15q15.
CLINICAL FEATURES
MacKinney et al. (1962) and Morton et al. (1962) studied 26 families.
They concluded that after the initial case in a family has been
identified, 4 tests suffice for the diagnosis in other family members:
smear, reticulocyte count, hemoglobin, and bilirubin. The fragility test
(increased osmotic fragility characterizes the disease) is unnecessary
after the diagnosis has been made in the proband. It was estimated that
the prevalence is 2.2 per 10,000, that the mutation rate is 0.000022 and
that about one-fourth of cases are sporadic. No evidence of reproductive
compensation or of increased prenatal and infant mortality was found. No
enzyme defect was identified (Miwa et al., 1962).
Several observations suggest that more than one type of hereditary
spherocytosis exists in man (review by Zail et al., 1967).
Barry et al. (1968) pointed out that hemochromatosis is a serious
complication of untreated spherocytosis. Fargion et al. (1986) described
2 brothers who were thought to be heterozygous for the hemochromatosis
gene and who also were affected with hereditary spherocytosis. Both had
severe iron overload whereas all relatives without hereditary
spherocytosis, including those with HLA haplotypes identical to those of
the 2 brothers, had normal iron stores. Montes-Cano et al. (2003)
reported a similar situation in a Spanish family: 3 members of different
generations were diagnosed with hereditary spherocytosis and 1 of them,
44 years of age, presented iron overload with hepatic deposit and
required treatment with periodic phlebotomies. Other members of the
family showed normal values in iron metabolism. The patient with iron
overload was a compound heterozygote for the H63D (235200.0002) and
C282Y (235200.0001) mutations in the HFE gene.
In a family with 6 persons affected in 3 generations, Wiley and Firkin
(1970) found a form of hereditary spherocytosis with unusual features;
other reports of atypical disease were reviewed.
Aksoy et al. (1974) described severe hemolytic anemia in a patient
seemingly with both elliptocytosis (inherited probably from the father)
and spherocytosis (inherited from the mother). This finding raises a
question of possible allelism of spherocytosis and one form of
elliptocytosis. A genetic compound is more likely to show summation of
effects than is a double heterozygote.
Epidemic aplastic crisis in congenital chronic hemolytic anemias has
been attributed to the human parvovirus (HPV) which also causes erythema
infectiosum, or fifth disease (Tsukada et al., 1985; Rao et al., 1983).
Lefrere et al. (1986) showed that in both children and adults the human
parvovirus can precipitate aplastic crisis in hereditary spherocytosis
just as it does in other forms of hereditary hemolytic anemia,
particularly sickle cell disease. Healthy persons probably develop an
erythroblastopenia when experiencing their first contact with HPV, but
this escapes notice when the normal red cell life span allows
maintenance of hemoglobin level throughout the interruption of red cell
production. Ng et al. (1987) described a father and a son in whom
aplastic crisis in hereditary spherocytosis was precipitated by
parvovirus infection.
Moiseyev et al. (1987) described a kindred in which hereditary
spherocytosis occurred in combination with hypertrophic cardiomyopathy
in 5 individuals in 4 successive generations. In another branch of the
family, 4 individuals in 3 successive generations had either hereditary
spherocytosis or hypertrophic cardiomyopathy (192600), but not both.
Coetzer et al. (1988) described a 41-year-old man and an unrelated
49-year-old woman who had atypical, severe spherocytosis with partial
response to splenectomy. No information on the family aided in
evaluating inheritance in the second case; in the first case, the
deceased father had had chronic anemia and a sib had died at age 3
months of unknown cause. In these 2 patients, the authors found a
partial deficiency of ankyrin and spectrin in red cells. Coetzer et al.
(1988) concluded that a defect in synthesis of ankyrin was the primary
abnormality.
In the offspring of first-cousin parents, both of whom had hereditary
spherocytosis, Duru et al. (1992) observed a 6-month-old male infant
with severe anemia. The infant required red blood cell transfusions
starting at the age of 1 month and continuing until splenectomy was
performed at the age of 1 year to produce a complete hematologic
remission. Duru et al. (1992) concluded that this represented an example
of homozygosity for the spherocytosis gene, presumably an ankyrin
mutant, and that splenectomy can cure the anemia, even in the
homozygote.
Both sickle cell anemia and hereditary spherocytosis are known causes of
leg ulcers. Peretz et al. (1997) reported the case of an 18-year-old
Bedouin with leg ulcers of 12-months duration; past history revealed HS
since childhood. Treatment for 6 months with various conservative
modalities had no effect on the ulcers. However, complete clearance was
achieved 2 months after splenectomy.
The precocious formation of bilirubinate gallstones is the most common
complication of hereditary spherocytosis, and the prevention of this
problem represents a major impetus for splenectomy in many patients with
compensated hemolysis. Because Gilbert syndrome (143500) had been
considered a risk factor for gallstone formation, Miraglia del Giudice
et al. (1999) postulated that the association of this common inherited
disorder of hepatic bilirubin metabolism with hereditary spherocytosis
could increase cholelithiasis. To test this hypothesis, 103 children
with mild to moderate hereditary spherocytosis who, from age 1 year, had
undergone a liver and biliary tree ultrasonography every year, were
retrospectively examined. The 2-bp TA insertion within the promoter of
the UGT1A1 gene (191740.0011), which is associated with Gilbert
syndrome, was screened. The risk of developing gallstones was
statistically different among the 3 groups of patients (homozygotes for
the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele
with the TA insertion). Miraglia del Giudice et al. (1999) concluded
that although patients with hereditary spherocytosis were the only ones
studied, extrapolating these findings to patients who have different
forms of inherited (e.g., thalassemia, intraerythrocytic enzymatic
deficiency) or acquired (e.g., autoimmune hemolytic anemia, hemolysis
from mechanical heart valve replacement) chronic hemolysis may be
warranted.
- Reviews
Davies and Lux (1989) gave a useful review of hereditary disorders of
the red cell membrane skeleton. They referred to a form of spherocytosis
due to a defect in ankyrin as spherocytosis-1 and a form due to a defect
in beta-spectrin as spherocytosis-2.
Perrotta et al. (2008) reviewed the several forms of hereditary
spherocytosis.
DIAGNOSIS
On behalf of the General Haematology Task Force of the British Committee
for Standards in Haematology, Bolton-Maggs et al. (2004) provided
comprehensive guidelines for the diagnosis and management of hereditary
spherocytosis.
CYTOGENETICS
Kimberling et al. (1975) demonstrated linkage between spherocytosis and
a translocation involving the short arms of chromosomes 8 and 12. They
concluded that the spherocytosis locus is either very close to the
centromere of chromosome 8 or on 12p. Kimberling et al. (1978) reported
further on their studies of a family with HS and an 8-12 translocation.
They concluded that a locus for HS is located near the breakpoint of the
translocation.
Cohen et al. (1991) described 2 sibs in whom congenital spherocytosis
was associated with an inherited interstitial deletion of 8p,
del8(p11-p21). This abnormal chromosome was inherited from their mother
who showed this deletion as well as a small fragment representing the
deleted segment. Centromeric material from chromosome 8 was detected in
this chromosome fragment by in situ hybridization using an
alpha-satellite probe, but not by C banding. Chromosome analysis of skin
fibroblasts from the mother and a third sib, both normal but with a
similar karyotype, showed the deleted fragment in over 80% of cells.
Since the chromosome abnormality was not observed in 5 of the mother's
sibs, it probably arose de novo in her. The 2 sibs with congenital
spherocytosis had multiple other phenotypic abnormalities. The male had
short stature, severe mental retardation, microcephaly, and micrognathia
with bat ears, primary failure of sexual development, and bilateral
conductive deafness secondary to congenital stapedial fixation. In
addition to these features, the sister had torticollis associated with
fusion of several vertebrae; she developed diabetes mellitus at the age
of 15 years, which was controlled by diet and chlorpropamide.
Stratton et al. (1992) described an infant with a de novo interstitial
deletion of the proximal short arm of chromosome 8 (p21p11.2). The
infant had bilateral cleft lip and palate and apparent hypogonadism.
Four previous reports of similar deletions (p21p11.1) were associated
with hypogonadotropic hypogonadism and hereditary spherocytosis. Since
their patient demonstrated no red blood cell abnormality, Stratton et
al. (1992) suggested that the gene for HS is located in the region
8p11.2-p11.1.
Bass et al. (1983) presented evidence for the chromosome 8 localization
of a spherocytosis locus: they observed mother and son with hereditary
spherocytosis and a balanced translocation between chromosomes 3 and 8.
The breakpoint on 8 in the family of Kimberling et al. (1975) and in
their family was at 8p11.
Chilcote et al. (1987) studied 2 dysmorphic sibs with neurologic
findings and hemolytic anemia. Clinical and laboratory findings were
consistent with the diagnosis of congenital spherocytosis whereas both
parents and 2 unaffected sibs were normal. The 2 affected children had
an interstitial deletion of the short arm of chromosome 8,
46,XX,del(8)(p11.1p21.1). Chilcote et al. (1987) suggested that together
with the evidence from the families of Kimberling et al. (1975) and Bass
et al. (1983), their family provides strong evidence for a gene for
congenital spherocytosis in the proximal part of 8p. Glutathione
reductase (GSR; 138300) levels were slightly reduced in the 2 affected
children relative to their parents and an unaffected sib but did not
approach the half-normal values that might be expected and it was
unlikely that the moderate reduction in the glutathione reductase
activity would cause hemolysis. The presence of abnormalities in 2 sibs
with normal parents may have its explanation in mosaicism of 1 parent.
Close linkage to GSR, which is at 8p21, was excluded by the family of
Nakashima et al. (1978).
Kitatani et al. (1988) studied a 1-year-old boy with spherocytosis
associated with a de novo minute deletion involving 8p21.1-p11.22.
Contradictory information on the mapping of hereditary spherocytosis may
reflect genetic heterogeneity in this condition as in elliptocytosis.
Costa et al. (1990) identified reports of 5 cases of deletion or
translocation involving chromosome 8p and leading to spherocytosis.
Lux et al. (1990) reported that 1 copy of the ankyrin gene was missing
from DNA of 2 unrelated children with severe spherocytosis and
heterozygous deletion of chromosome 8--del(8)(p11-p21.1). Affected red
cells were also ankyrin-deficient.
Okamoto et al. (1995) described a 30-month-old Japanese boy with
spherocytic anemia in association with multiple anomalies and mental
retardation. The karyotype had a deletion of interstitial deletion of
8p: del(8)(p11.23p21.1). Glutathione reductase activity was moderately
reduced, consistent with deletion of that locus as well as of the
ankyrin locus. Okamoto et al. (1995) reviewed the other cases of 8p
deletion associated with spherocytic anemia.
PATHOGENESIS
Jacob and Jandl (1964) were of the view that the primary defect is in
the red cell membrane, which is abnormally permeable to sodium.
Jacob et al. (1971) demonstrated altered membrane protein in hereditary
spherocytosis. Microfilamentous proteins resembling actin are important
to the shape of the red cell. Comparable membrane proteins occur
throughout phylogeny under circumstances suggesting a role in cell
plasticity and shape. Actin and myosin-like filamentous proteins occur
in platelets.
Heterogeneity in hereditary spherocytosis was indicated by studies of
structural proteins of the red cell membrane, including alpha and beta
spectrin,. actin (see 102630), and protein 4.1 (EPB41; 130500). In a
systematic assay of the interactions of spectrin in 6 kindreds with
autosomal dominant hereditary spherocytosis, Wolfe et al. (1982) found 1
in which all 4 affected members had reduced enhancement of
spectrin-actin binding by protein 4.1, owing to a 39% decrease in the
binding of normal protein 4.1 by spectrin. The defective spectrin was
separated into 2 populations by affinity chromatography on immobilized
normal protein 4.1. One population lacked ability to bind 4.1, but the
other functioned normally.
Hill et al. (1982) concluded that 'the difference between HS and normal
membranes, which persists in isolated cytoskeletons, suggests that
alterations in either the primary structure or the degree of
phosphorylation of protein bands 2.1 or 4.1 may be central to the
molecular basis of hereditary spherocytosis.' The 2.1 band is also known
as ankyrin. The major proteins of the cytoskeleton, spectrin and actin,
are attached to the cell membrane by bands 2.1 and 4.1. Johnsson and
Himberg (1982) presented evidence that platelets, as well as red cells,
are defective in HS.
In a 41-year old man with severe spherocytosis, Coetzer et al. (1988)
studied the synthesis, assembly, and turnover of spectrin and ankyrin in
the reticulocytes of the first patient. The synthesis of spectrin, when
measured in the cell cytosol, was normal (alpha-spectrin; 182860) or
increased (beta-spectrin; 182870). The principal defect appeared to be a
diminished incorporation of ankyrin into the cell membrane, leading to
decreased deposition of spectrin as a secondary phenomenon. Ankyrin is
the principal binding site for spectrin on the membrane. Normal red
cells contain 1 copy of ankyrin per spectrin tetramer. The red cell
membrane skeleton is a submembranous network composed mainly of
spectrin, actin, and proteins that migrate on gel electrophoresis as
bands 4.1 (EPB41; 130500) and 4.9 (EPB49; 125305). Visualization of the
skeleton by electron microscopy shows a primarily hexagonal lattice of
fibers of spectrin tetramers linked to junctional complexes containing
actin and proteins 4.1 and 4.9. The skeleton is attached to the cell
membrane by ankyrin (protein 2.1), which connects beta-spectrin to the
cytoplasmic portion of band 3 (SLC4A1; 109270), which is the major
integral membrane protein. In addition, protein 4.1 links the distal
ends of spectrin tetramers to transmembrane glycoprotein.
Hanspal et al. (1991) concluded that the primary defect underlying the
combined spectrin and ankyrin deficiency in severe hereditary
spherocytosis is a deficiency of ankyrin mRNA leading to a reduced
synthesis of ankyrin, which, in turn, underlies a decreased assembly of
spectrin on the membrane.
MAPPING
Using RFLPs defined by a cDNA for human erythrocyte ankyrin, Forget et
al. (1989) demonstrated close linkage between hereditary spherocytosis
and the ankyrin gene, with no crossovers observed. The calculated lod
score was 3.63 at a theta of 0.0. The ankyrin gene appears to be located
on the short arm of chromosome 8. The large kindred in which the linkage
was established had classic features.
Costa et al. (1990) analyzed a large kindred with typical dominant
hereditary spherocytosis for genetic linkage with the genes for alpha
spectrin, beta spectrin, protein 4.1, and ankyrin by means of RFLPs.
Close linkage was excluded for all of the candidate genes except that
for ankyrin, which was found to show no recombination, with a lod score
of 3.63.
By fluorescence-based in situ hybridization, Tse et al. (1990) localized
the ankyrin gene to 8p11.2.
MOLECULAR GENETICS
Davies and Lux (1989) stated that dosage analysis in 2 hereditary
spherocytosis patients with chromosome 8p11 deletions showed them to be
hemizygous for the ankyrin gene. A corresponding reduction of
approximately 50% in the amount of ankyrin protein was also seen in
these patients, who had mental retardation in addition to the red cell
defect. In both normoblastosis mice and hereditary spherocytosis humans,
spectrin is also reduced as a secondary phenomenon.
Iolascon et al. (1991) described 2 Italian families with ankyrin
deficiency spherocytosis. In both, the disorder was a new mutation in
the proband; 1 proband transmitted it to an offspring.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime
untranslated/promoter region of ankyrin-1 and the 19 coding exons of
band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They
identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense
mutations and a mutation in the putative ankyrin-1 promoter were common
in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3
frameshift and nonsense null mutations prevailed in dominant HS.
Increased accumulation of the normal protein product partially
compensated for the ankyrin-1 or band 3 defects in some of these null
mutations. The findings indicated to Eber et al. (1996) that ankyrin-1
mutations are a major cause of dominant and recessive HS (between 35 and
65%), that band 3 mutations are less common (between 15 and 25%), and
that the severity of HS is modified by factors other than the primary
gene defect.
Gallagher and Forget (1998) tabulated a total of 34 mutations in the
ANK1 gene that have been associated with hereditary spherocytosis, as
contrasted with 2 mutations in the alpha-spectrin gene and 19 in the
beta-spectrin gene.
In the proband reported by Duru et al. (1992), Edelman et al. (2007)
identified a homozygous splice site mutation in the ANK1 gene
(612641.0007). Each parent was heterozygous for the mutation.
ANIMAL MODEL
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb
locus maps to mouse chromosome 8 in a segment that shows homology of
synteny with human 8p (White and Barker, 1987). White et al. (1990) used
immunologic and biochemical methods to demonstrate an altered (150 kD)
immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+)
reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia,
significant neurologic dysfunction associated with Purkinje cell
degeneration in the cerebellum and the development of a late-onset
neurologic syndrome characterized by persistent tremor and gait
disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin
(HBG1; 142200) reporter gene in an erythroid-specific,
position-independent, copy number-dependent fashion in transgenic mice
to study spherocytosis-associated promoter mutations. They detected
abnormalities in reporter gene mRNA and protein expression. Mice with
the wildtype promoter demonstrated normal expression in all
erythrocytes, whereas mice with the -108T-C promoter mutation
(612641.0002) demonstrated varied expression. Undetectable or
significantly lower expression was found in mice with linked -108T-C and
-153G-A (612641.0006) promoter mutations. Gallagher et al. (2001)
concluded that functional defects can be caused by HS-related ankyrin
gene promoter mutations.
HISTORY
Sengar et al. (1977) presented some fragmentary evidence that HLA and
hereditary spherocytosis may be linked.
De Jongh et al. (1982) could demonstrate no linkage of spherocytosis
with Gm or with HLA. Lod scores with PI were also negative.
*FIELD* SA
Gallagher and Forget (1998); Jacob (1968); Jacob (1966); Jacob
(1965); Jacob et al. (1971); Jandl and Cooper (1972); Jensson et al.
(1977); Kirkpatrick et al. (1975); Lux et al. (1990); MacKinney (1965);
MacPherson et al. (1971); Masera et al. (1980); Mohler and Wheby (1986);
Mohler and Wheby (1984); Motulsky et al. (1962); Nozawa et al. (1974);
Reznikoff-Etievant et al. (1980); Shohet (1979); Wichterle et al.
(1996); Wiley (1972)
*FIELD* RF
1. Aksoy, M.; Erdem, S.; Dincol, G.; Erdogan, G.; Cilingiroglu, K.;
Dincol, K.: Combination of hereditary elliptocytosis and hereditary
spherocytosis. Clin. Genet. 6: 46-50, 1974.
2. Barry, M.; Scheuer, P. J.; Sherlock, S.; Ross, C. F.; Williams,
R.: Hereditary spherocytosis with secondary haemochromatosis. Lancet 292:
481-485, 1968. Note: Originally Volume II.
3. Bass, E. B.; Smith, S. W., Jr.; Stevenson, R. E.; Rosse, W. F.
: Further evidence for location of the spherocytosis gene on chromosome
8. Ann. Intern. Med. 99: 192-193, 1983.
4. Bolton-Maggs, P. H. B.; Stevens, R. F.; Dodd, N. J.; Lamont, G.;
Tittensor, P.; King, M.-J.: Guidelines for the diagnosis and management
of hereditary spherocytosis. Brit. J. Haemat. 126: 455-474, 2004.
5. Chilcote, R. R.; Le Beau, M. M.; Dampier, C.; Pergament, E.; Verlinsky,
Y.; Mohandas, N.; Frischer, H.; Rowley, J. D.: Association of red
cell spherocytosis with deletion of the short arm of chromosome 8. Blood 69:
156-159, 1987.
6. Coetzer, T. L.; Lawler, J.; Liu, S.-C.; Prchal, J. T.; Gualtieri,
R. J.; Brain, M. C.; Dacie, J. V.; Palek, J.: Partial ankyrin and
spectrin deficiency in severe, atypical hereditary spherocytosis. New
Eng. J. Med. 318: 230-234, 1988.
7. Cohen, H.; Walker, H.; Delhanty, J. D. A.; Lucas, S. B.; Huehns,
E. R.: Congenital spherocytosis, B19 parvovirus infection and inherited
interstitial deletion of the short arm of chromosome 8. Brit. J.
Haemat. 78: 251-257, 1991.
8. Costa, F. F.; Agre, P.; Watkins, P. C.; Winkelmann, J. C.; Tang,
T. K.; John, K. M.; Lux, S. E.; Forget, B. G.: Linkage of dominant
hereditary spherocytosis to the gene for the erythrocyte membrane-skeleton
protein ankyrin. New Eng. J. Med. 323: 1046-1050, 1990.
9. Davies, K. A.; Lux, S. E.: Hereditary disorders of the red cell
membrane skeleton. Trends Genet. 5: 222-227, 1989.
10. de Jongh, B. M.; Blacklock, H. A.; Reekers, P.; Volkers, W. S.;
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hereditary spherocytosis (SPH) and genetic markers including HLA and
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for dominant form of hereditary spherocytosis. Brit. J. Haemat. 82:
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13. Eber, S. W.; Gonzalez, J. M.; Lux, M. L.; Scarpa, A. L.; Tse,
W. T.; Dornwell, M.; Herbers, J.; Kugler, W.; Ozcan, R.; Pekrun, A.;
Gallagher, P. G.; Schroter, W.; Forget, B. G.; Lux, S. E.: Ankyrin-1
mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature
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14. Edelman, E. J.; Maksimova, Y.; Duru, F.; Altay, C.; Gallagher,
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molecular basis of erythrocyte shape. Science 234: 1217-1223, 1986.
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18. Gallagher, P. G.; Forget, B. G.: Hematologically important mutations:
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ankyrin promoter mutations associated with recessive hereditary spherocytosis
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21. Hanspal, M.; Yoon, S.-H.; Yu, H.; Hanspal, J. S.; Lambert, S.;
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27. Jacob, H. S.; Amsden, T.; White, J.: Experimental production
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35. Kirkpatrick, F. H.; Woods, G. M.; LaCelle, P. L.: Absence of
one component of spectrin adenosine triphosphatase in hereditary spherocytosis. Blood 46:
945-954, 1975.
36. Kitatani, M.; Chiyo, H.; Ozaki, M.; Shike, S.; Miwa, S.: Localization
of the spherocytosis gene to chromosome segment 8p11.22-8p21.1. Hum.
Genet. 78: 94-95, 1988.
37. Lefrere, J. J.; Courouce, A.-M.; Girot, R.; Bertrand, Y.; Soulier,
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infection. Brit. J. Haemat. 62: 653-658, 1986.
38. Lux, S. E.; John, K. M.; Bennett, V.: Analysis of cDNA for human
erythrocyte ankyrin indicates a repeated structure with homology to
tissue-differentiation and cell-cycle control proteins. Nature 344:
36-42, 1990.
39. Lux, S. E.; Tse, W. T.; Menninger, J. C.; John, K. M.; Harris,
P.; Shalev, O.; Chilcote, R. R.; Marchesi, S. L.; Watkins, P. C.;
Bennett, V.; McIntosh, S.; Collins, F. S.; Francke, U.; Ward, D. C.;
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of human erythrocyte ankyrin gene on chromosome 8. Nature 345: 736-739,
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40. MacKinney, A. A.: Hereditary spherocytosis: clinical family studies. Arch.
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41. MacKinney, A. A.; Morton, N. E.; Kosower, N. S.; Schilling, R.
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statistical analysis of multiple laboratory tests. J. Clin. Invest. 41:
554-567, 1962.
42. MacPherson, A. I. S.; Richmond, J.; Donaldson, G. W. K.; Muir,
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43. Masera, G.; Mieli, G.; Petrone, M.; Porcelli, P.: Transient aplastic
crisis in hereditary spherocytosis. Acta Haemat. 63: 28-31, 1980.
44. Miraglia del Giudice, E.; Perrotta, S.; Nobili, B.; Specchia,
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risk for developing gallstones in patients with hereditary spherocytosis. Blood 94:
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45. Miwa, S.; Tanaka, K. R.; Valentine, W. N.: Enolase activity of
erythrocytes in hereditary spherocytosis. Nature 195: 613-614, 1962.
46. Mohler, D. N.; Wheby, M. S.: Hemochromatosis heterozygotes may
have significant iron overload when they also have hereditary spherocytosis. Am.
J. Med. Sci. 292: 320-324, 1986.
47. Mohler, D. N.; Wheby, M. S.: Patients with hereditary spherocytosis
may have clinically significant iron overload when they are also heterozygous
for hemochromatosis. Trans. Am. Clin. Climatol. Assoc. 96: 34-40,
1984.
48. Moiseyev, V. S.; Korovina, E. A.; Polotskaya, E. L.; Poliyanskaya,
I. S.; Yazdovsky, V. V.: Hypertrophic cardiomyopathy associated with
hereditary spherocytosis in three generations of one family. (Letter) Lancet 330:
853-854, 1987. Note: Originally Volume II.
49. Montes-Cano, M. A.; Rodriguez-Munoz, F.; Franco-Osorio, R.; Nunez-Roldan,
A.; Gonzalez-Escribano, M. F.: Hereditary spherocytosis associated
with mutations in HFE gene. Ann. Hematol. 82: 769-772, 2003.
50. Morton, N. E.; MacKinney, A. A.; Kosower, N. S.; Schilling, R.
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170-184, 1962.
51. Motulsky, A. G.; Anderson, R.; Sparkes, R. S.; Huestis, R. H.
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52. Nakashima, K.; Yamauchi, K.; Miwa, S.; Fujimura, K.; Mizutani,
A.; Kuramoto, A.: Glutathione reductase deficiency in a kindred with
hereditary spherocytosis. Am. J. Hemat. 4: 141-150, 1978.
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spherocytosis revealed by human parvovirus infection.(Letter) Brit.
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54. Nozawa, Y.; Noguchi, T.; Iida, H.; Fukushima, H.; Sekiya, T.;
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55. Okamoto, N.; Wada, Y.; Nakamura, Y.; Nakayama, M.; Chiyo, H.;
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Lux, S. E.; Otto, E.; Bennett, V.; Higgins, A.; Barker, J. E.: Purkinje
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nb/nb mice. J. Cell Biol. 114: 1233-1241, 1991.
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60. Reznikoff-Etievant, M. F.; Bonaiti, C.; Maigret, P.; Malvoisin,
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61. Sengar, D. P. S.; McLeish, W. A.; Smiley, R. K.; Luke, B.: HLA
and hereditary spherocytosis. Vox Sang. 33: 278-279, 1977.
62. Shohet, S. B.: Reconstitution of spectrin-deficient spherocytic
mouse erythrocyte membranes. J. Clin. Invest. 64: 483-494, 1979.
63. Stratton, R. F.; Crudo, D. F.; Varela, M.; Shapira, E.: Deletion
of the proximal short arm of chromosome 8. Am. J. Med. Genet. 42:
15-18, 1992.
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Shibata, A.; Nunoue, T.: Epidemic of aplastic crisis in patients
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only, 1985. Note: Originally Volume 1.
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71. Wolfe, L. C.; John, K. M.; Falcone, J. C.; Byrne, A. M.; Lux,
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Atypical hereditary spherocytosis: biochemical studies and sites of
erythrocyte destruction. Brit. J. Haemat. 13: 323-334, 1967.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Liver];
Jaundice;
[Biliary tract];
Gallstones;
[Spleen];
Splenomegaly
HEMATOLOGY:
Spherocytosis;
Hemolytic anemia;
Reticulocytosis
LABORATORY ABNORMALITIES:
Increased reticulocyte count;
Hyperbilirubinemia;
Increased osmotic fragility;
Negative direct antiglobulin (Coombs) test;
Elevated MCHC
MISCELLANEOUS:
Autosomal recessive inheritance can occur;
Patients with homozygous mutations have a more severe disorder
MOLECULAR BASIS:
Caused by mutation in the ankyrin 1 gene (ANK1, 182900.0001);
Caused by mutation in the spectrin beta-1 gene (SPTB, 182870.0010);
Caused by mutation in the erythrocytic protein 4.2 gene (EPB42, 177070.0001);
Caused by mutation in the red cell membrane band 3 gene (BND3, 109270.0003)
*FIELD* CN
Cassandra L. Kniffin - updated: 9/17/2007
Kelly A. Przylepa - revised: 9/19/2000
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/24/2011
ckniffin: 9/17/2007
joanna: 5/24/2002
kayiaros: 9/19/2000
*FIELD* CN
Carol A. Bocchini - updated: 2/26/2009
George E. Tiller - updated: 1/23/2009
Cassandra L. Kniffin - updated: 9/17/2007
Victor A. McKusick - updated: 10/20/2004
Victor A. McKusick - updated: 1/23/2004
Paul J. Converse - updated: 1/18/2002
Victor A. McKusick - updated: 4/6/2001
Paul J. Converse - updated: 6/8/2000
Victor A. McKusick - updated: 1/6/2000
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 3/31/1998
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
terry: 04/06/2011
carol: 3/23/2011
terry: 5/4/2009
terry: 3/24/2009
carol: 3/24/2009
carol: 3/18/2009
carol: 3/11/2009
carol: 3/10/2009
terry: 2/26/2009
carol: 2/26/2009
terry: 2/9/2009
wwang: 1/23/2009
carol: 12/8/2008
mgross: 2/21/2008
wwang: 9/24/2007
ckniffin: 9/17/2007
tkritzer: 10/22/2004
terry: 10/20/2004
carol: 3/17/2004
tkritzer: 1/29/2004
terry: 1/23/2004
terry: 11/24/2003
terry: 3/6/2002
mgross: 1/18/2002
mcapotos: 4/11/2001
mcapotos: 4/6/2001
terry: 4/6/2001
carol: 10/20/2000
carol: 6/8/2000
mgross: 1/12/2000
terry: 1/6/2000
terry: 3/1/1999
carol: 2/27/1999
dkim: 9/11/1998
dkim: 7/17/1998
carol: 7/16/1998
terry: 7/13/1998
terry: 6/3/1998
psherman: 3/31/1998
terry: 3/26/1998
alopez: 6/3/1997
mark: 7/22/1996
mark: 5/31/1996
terry: 5/29/1996
mark: 9/14/1995
mimadm: 3/25/1995
davew: 8/1/1994
carol: 2/19/1993
carol: 12/23/1992
carol: 10/23/1992
MIM
612641
*RECORD*
*FIELD* NO
612641
*FIELD* TI
*612641 ANKYRIN 1; ANK1
;;ANKYRIN, ERYTHROCYTIC
ANKYRIN-R, INCLUDED; ANK, INCLUDED;;
read moreANKYRIN 1 MUSCLE-SPECIFIC ISOFORM, INCLUDED
*FIELD* TX
CLONING
By analysis of cDNA for human erythroid ankyrin, Lux et al. (1990)
determined that the mature protein contains 1,880 amino acids comprising
an N-terminal domain binding integral membrane proteins and tubulin, a
central domain binding spectrin and vimentin, and an acidic C-terminal
'regulatory' domain containing an alternatively spliced sequence missing
from ankyrin variant 2.2. The N-terminal domain is composed almost
entirely of 22 tandem 33-amino acid repeats.
Lambert et al. (1990) found that the cDNA sequence has a large open
reading frame of 5,636 basepairs coding for a polypeptide of 1,879 amino
acids for the predicted molecular mass of 206 kD. Ankyrin comprises a
band-3 (SLC4A1; 109270)-binding domain, a spectrin-binding domain, and a
regulatory domain. The band-3-binding domain consists of 23 homologous
repeats, each 33 amino acids in length. The regulatory domain differs in
length in the 2 isoforms of ankyrin, proteins 2.1 and 2.2.
By Northern blot analysis of human skeletal muscle tissue with an
erythroid ANK1 probe, Gallagher and Forget (1998) detected expression of
2.3- and 1.6-kb transcripts, much smaller than the 7.3- and 9.0-kb
transcripts observed in erythroid tissue RNA. Using a 5-prime RACE
skeletal muscle product as probe, they identified a cDNA encoding a
155-amino acid protein. Secondary structure analysis predicted the
presence of a highly charged N-terminal domain followed by a C-terminal
domain composed of alternating alpha helix and beta sheet. The
membrane-binding domain, the spectrin/fodrin-binding domain, and most of
the regulatory domains found in the erythroid form of ANK1 are missing.
Genomic sequence analysis determined that the smaller transcript
contains 4 exons, a novel exon 1 followed by the erythroid exons 40, 41,
and 42, spread over approximately 10 kb. Exon 1 is located in intron 39
of the erythroid ANK gene. Northern blot analysis revealed abundant
expression of the 2.3- and 1.6-kb transcripts restricted to skeletal and
cardiac muscle with lesser amounts of 3.7- and 7.0-kb transcripts.
Immunoblot analysis showed that muscle ANK1 is readily detected as 28-
and 30-kD proteins in skeletal muscle but that detection of 70-kD and
210-kD proteins in erythrocyte membranes requires prolonged exposure.
GENE STRUCTURE
Tse et al. (1990) described the structure of the ANK1 gene corresponding
to the domain structure of the protein.
MAPPING
By fluorescence-based in situ hybridization, Tse et al. (1990) localized
the ankyrin gene to 8p11.2. Lux et al. (1990) independently reported
localization of ANK1 to chromosome 8p11.2 by FISH analysis.
MOLECULAR GENETICS
Davies and Lux (1989) stated that dosage analysis in 2 hereditary
spherocytosis patients with chromosome 8p11 deletions showed them to be
hemizygous for the ankyrin gene. A corresponding reduction of
approximately 50% in the amount of ankyrin protein was also seen in
these patients, who had mental retardation in addition to the red cell
defect. In both normoblastosis mice and hereditary spherocytosis humans,
spectrin is also reduced as a secondary phenomenon.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime
untranslated/promoter region of ankyrin-1 and the 19 coding exons of
band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They
identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense
mutations and a mutation in the putative ankyrin-1 promoter were common
in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3
frameshift and nonsense null mutations prevailed in dominant HS.
Increased accumulation of the normal protein product partially
compensated for the ankyrin-1 or band 3 defects in some of these null
mutations. The findings indicated to Eber et al. (1996) that ankyrin-1
mutations are a major cause of dominant and recessive HS (between 35 and
65%), that band 3 mutations are less common (between 15 and 25%), and
that the severity of HS is modified by factors other than the primary
gene defect.
In the proband reported by Duru et al. (1992), Edelman et al. (2007)
identified a homozygous splice site mutation in the ANK1 gene
(612641.0007). Each parent was heterozygous for the mutation.
ANIMAL MODEL
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb
locus maps to mouse chromosome 8 in a segment that shows homology of
synteny with human 8p (White and Barker, 1987). White et al. (1990) used
immunologic and biochemical methods to demonstrate an altered (150 kD)
immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+)
reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia,
significant neurologic dysfunction associated with Purkinje cell
degeneration in the cerebellum and the development of a late-onset
neurologic syndrome characterized by persistent tremor and gait
disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin
(HBG1; 142200) reporter gene in an erythroid-specific,
position-independent, copy number-dependent fashion in transgenic mice
to study spherocytosis-associated promoter mutations. They detected
abnormalities in reporter gene mRNA and protein expression. Mice with
the wildtype promoter demonstrated normal expression in all
erythrocytes, whereas mice with the -108T-C promoter mutation
(612641.0002) demonstrated varied expression. Undetectable or
significantly lower expression was found in mice with linked -108T-C and
-153G-A (612641.0006) promoter mutations. Gallagher et al. (2001)
concluded that functional defects can be caused by HS-related ankyrin
gene promoter mutations.
Salomao et al. (2010) found that glycophorin C (GPC; see 110750)
partitioning was unperturbed in nb/nb cells: GPC sorted to nascent
reticulocytes in both wildtype and nb/nb enucleating erythroblasts. In
addition, glycophorin A (GPA; see 111300), band 3 (SLC4A1; 109270), and
Rh antigen (RH; 111700) distributed predominantly to reticulocytes in
wildtype enucleating erythroblasts. However, band 3, GPA, and Rh antigen
sorted to both expelled nuclei and reticulocytes in nb/nb enucleating
erythroblasts. The findings demonstrated that, in mature nb/nb red
cells, a mechanism involving abnormal sorting during nuclear extrusion
results in multiple protein deficiencies. Salomao et al. (2010) also
raised the possibility that reticulocytes in hereditary spherocytosis
may differ from normal reticulocytes in their biophysical properties of
membrane cohesion or membrane deformability. The results also showed
that cytoskeletal attachments are an important factor in regulating
transmembrane protein sorting to reticulocytes.
*FIELD* AV
.0001
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN-RAKOVNIK
ANK1, GLU1669TER
In a kindred with autosomal dominant hereditary spherocytosis (182900),
Jarolim et al. (1995) identified a unique mutation in the regulatory
domain of ankyrin associated with a marked and selective deficiency of
ankyrin isoform 2.1 and a normal content of ankyrin isoform 2.2. The
deficiency of the 2.1 ankyrin isoform was accompanied by a proportional
deficiency of spectrin. The genetic defect was a nonsense mutation
glu1669-to-ter (GAA-to-TAA) in 1 allele of the ANK1 gene. Only normal
2.1 mRNA was detected in the reticulocyte RNA. The regulatory domain of
ankyrin is subject to extensive alternative splicing. In the case of
this mutation, alternative splicing within the regulatory domain of
ankyrin retained codon 1669 in ankyrin 2.1 mRNA and removed it from
ankyrin 2.2 mRNA. Jarolim et al. (1995) proposed that the glu1669-to-ter
mutation decreased the stability of the abnormal ankyrin 2.1 mRNA
allele, leading to a decreased synthesis of ankyrin 2.1 and a secondary
deficiency of spectrin. The mutant ankyrin was named for the city of
origin, Rakovnik, in the Czech Republic.
.0002
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, -108T-C
Eber et al. (1996) found that the ankyrin-1 promoter mutation, -108
T-to-C, is particularly common in recessive hereditary spherocytosis
(182900). The mutation lies immediately upstream of a first (minor)
transcription start site in the promoter region. They stated that
because the mutation is silent in heterozygotes, patients with recessive
HS must have a second mutation in the other allele. In 1 patient this
was a missense mutation, V463I, in the band-3-binding domain of
ankyrin-1. Notably, the patient's red cells were more deficient in band
3 than in ankyrin-1 or spectrin (182860), which is opposite to the trend
in other ankyrin-1 defects. The second mutation in another patient
created an amino acid change in a rare alternate splice product and
potentially a cryptic 5-prime splice site.
.0003
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN SAINT-ETIENNE 1
ANK1, TRP1721TER
In a kindred with autosomal dominant hereditary spherocytosis (182900),
Hayette et al. (1998) described a TGG-to-TGA transition in exon 39 of
the ANK1 gene resulting in a trp1721-to-ter stop mutation and truncation
of the ankyrin protein.
.0004
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN SAINT-ETIENNE 2
ANK1, ARG1833TER
In 2 families with autosomal dominant hereditary spherocytosis (182900),
Hayette et al. (1998) identified heterozygosity for an ANK1 truncating
mutation: codon 1833 in exon 41 was converted from CGA (arg) to TGA
(stop).
.0005
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN FLORIANOPOLIS
ANK1, 1-BP INS, 506C
In 3 unrelated probands from different ethnic backgrounds who had severe
hereditary spherocytosis (182900) requiring splenectomy, Gallagher et
al. (2000) found the same frameshift mutation in exon 4, insertion of an
extra cytosine nucleotide at codon 506 of the ANK1 gene. The patients
were of Italian, Portuguese, and German extraction and the mutation was
on a different haplotype in each.
.0006
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, -153G-A
Leite et al. (2000) identified a heterozygous G-to-A transition at
position -153 of the ANK1 promoter in a Brazilian kindred with
ankyrin-deficient recessive spherocytosis. The -153G-A mutation was
always found in cis with the -108C-T mutation (612641.0002), and these
linked mutations were silent in the heterozygous state.
.0007
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, IVS16AS, G-A, -17
In a Turkish boy with severe autosomal recessive spherocytosis (182900),
born of consanguineous parents, Edelman et al. (2007) identified a
homozygous G-to-A transition in intron 16 of the ANK1 gene
(IVS16AS-17G-A). The family had previously been reported by Duru et al.
(1992). Each parent, who had a milder form of spherocytosis, was
heterozygous for the mutation. Edelman et al. (2007) used denaturing
high-performance liquid chromatography (DHPLC) to identify the mutation.
RT-PCR of patient reticulocytes detected 9 abnormal splice isoforms of
ANK1 and no wildtype isoforms, indicating that the mutation interrupted
normal transcription.
.0008
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, 20-BP DEL, NT604
In a female German patient with moderate spherocytosis (182900), Eber et
al. (1996) identified a 20-bp deletion in exon 6 of the ANK1 gene,
resulting in frameshift and premature termination. Subsequently,
following reexamination of the patient, Gallagher et al. (2005)
identified compound heterozygosity for the 20-bp deletion and a 2-bp
deletion (-72delTG; 612641.0009) in the ANK1 promoter adjacent to a
transcription initiation site. Both parents had normal hematocrits,
increased reticulocyte counts, and abnormal erythrocyte incubated
osmotic fragility, typical for the diagnosis of HS with compensated
hemolysis. The mother carried the 20-bp deletion. The father was
presumed to carry the 2-bp deletion but was deceased, and there was no
genetic material available for testing. In vitro analysis of the mutant
promoter showed decreased levels of ANK1 expression, altered
transcription initiation site utilization and defective binding of
TATA-binding protein (TBP; 600075) and TFIID (TAF1; 313650) complex
formation. In a transgenic mouse model, the mutant ankyrin promoter led
to abnormalities in ANK1 expression, including decreased expression of a
reporter gene and altered transcription initiation site utilization. The
authors concluded that the promoter mutation altered ANK1 gene
transcription and contributes to the HS phenotype by decreasing ankyrin
gene synthesis via disruption of TFIID complex interactions with the
ankyrin core promoter. Gallagher et al. (2005) proposed that in
promoters that lack conserved cis elements, the TFIID complex may direct
preinitiation complex formation at specific sites in core promoter DNA.
.0009
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, 2-BP DEL, -72TG
See 612641.0008 and Gallagher et al. (2005).
*FIELD* RF
1. Davies, K. A.; Lux, S. E.: Hereditary disorders of the red cell
membrane skeleton. Trends Genet. 5: 222-227, 1989.
2. Duru, F.; Gurgey, A.; Ozturk, G.; Yorukan, S.; Altay, C.: Homozygosity
for dominant form of hereditary spherocytosis. Brit. J. Haemat. 82:
596-600, 1992.
3. Eber, S. W.; Gonzalez, J. M.; Lux, M. L.; Scarpa, A. L.; Tse, W.
T.; Dornwell, M.; Herbers, J.; Kugler, W.; Ozcan, R.; Pekrun, A.;
Gallagher, P. G.; Schroter, W.; Forget, B. G.; Lux, S. E.: Ankyrin-1
mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature
Genet. 13: 214-218, 1996.
4. Edelman, E. J.; Maksimova, Y.; Duru, F.; Altay, C.; Gallagher,
P. G.: A complex splicing defect associated with homozygous ankyrin-deficient
hereditary spherocytosis. Blood 109: 5491-5493, 2007.
5. Gallagher, P. G.; Ferreira, J. D. S.; Costa, F. F.; Saad, S. T.
O.; Forget, B. G.: A recurrent frameshift mutation of the ankyrin
gene associated with severe hereditary spherocytosis. Brit. J. Haemat. 111:
1190-1193, 2000.
6. Gallagher, P. G.; Forget, B. G.: An alternate promoter directs
expression of a truncated, muscle-specific isoform of the human ankyrin
1 gene. J. Biol. Chem. 273: 1339-1348, 1998.
7. Gallagher, P. G.; Nilson, D. G.; Wong, C.; Weisbein, J. L.; Garrett-Beal,
L. J.; Eber, S. W.; Bodine, D. M.: A dinucleotide deletion in the
ankyrin promoter alters gene expression, transcription initiation
and TFIID complex formation in hereditary spherocytosis. Hum. Molec.
Genet. 14: 2501-2509, 2005.
8. Gallagher, P. G.; Sabatino, D. E.; Basseres, D. S.; Nilson, D.
M.; Wong, C.; Cline, A. P.; Garrett, L. J.; Bodine, D. M.: Erythrocyte
ankyrin promoter mutations associated with recessive hereditary spherocytosis
cause significant abnormalities in ankyrin expression. J. Biol. Chem. 276:
41683-41689, 2001.
9. Hayette, S.; Carre, G.; Bozon, M.; Alloisio, N.; Maillet, P.; Wilmotte,
R.; Pascal, O.; Reynaud, J.; Reman, O.; Stephan, J.-L.; Morle, L.;
Delaunay, J.: Two distinct truncated variants of ankyrin associated
with hereditary spherocytosis. Am. J. Hemat. 58: 36-41, 1998.
10. Jarolim, P.; Rubin, H. L.; Brabec, V.; Palek, J.: A nonsense
mutation glu1669-to-ter within the regulatory domain of human erythroid
ankyrin leads to a selective deficiency of the major ankyrin isoform
(band 2.1) and a phenotype of autosomal dominant hereditary spherocytosis. J.
Clin. Invest. 95: 941-947, 1995.
11. Lambert, S.; Yu, H.; Prchal, J. T.; Lawler, J.; Ruff, P.; Speicher,
D.; Cheung, M. C.; Kan, Y. W.; Palek, J.: cDNA sequence for human
erythrocyte ankyrin. Proc. Nat. Acad. Sci. 87: 1730-1734, 1990.
12. Leite, R. C. A.; Basseres, D. S.; Ferreira, J. S.; Alberto, F.
L.; Costa, F. F.; Saad, S. T. O.: Low frequency of ankyrin mutations
in hereditary spherocytosis: identification of three novel mutations. Hum.
Mutat. 16: 529 only, 2000.
13. Lux, S. E.; John, K. M.; Bennett, V.: Analysis of cDNA for human
erythrocyte ankyrin indicates a repeated structure with homology to
tissue-differentiation and cell-cycle control proteins. Nature 344:
36-42, 1990.
14. Peters, L. L.; Birkenmeier, C. S.; Bronson, R. T.; White, R. A.;
Lux, S. E.; Otto, E.; Bennett, V.; Higgins, A.; Barker, J. E.: Purkinje
cell degeneration associated with erythroid ankyrin deficiency in
nb/nb mice. J. Cell Biol. 114: 1233-1241, 1991.
15. Salomao, M.; Chen, K.; Villalobos, J.; Mohandas, N.; An, X.; Chasis,
J. A.: Hereditary spherocytosis and hereditary elliptocytosis: aberrant
protein sorting during erythroblast enucleation. Blood 116: 267-269,
2010.
16. Tse, W. T.; Meninger, J.; Ward, D.; John, K.; Lux, S. E.; Forget,
B. G.: Genomic cloning and chromosomal sublocalization of the human
ankyrin gene.(Abstract) Clin. Res. 38: 266A, 1990.
17. White, R.; Barker, J.: Normoblastosis, a mutant mouse with severe
hemolytic anemia.(Abstract) Blood 70S: 57a, 1987.
18. White, R. A.; Birkenmeier, C. S.; Lux, S. E.; Barker, J. E.:
Ankyrin and the hemolytic anemia mutation, nb, map to mouse chromosome
8: presence of the nb allele is associated with a truncated erythrocyte
ankyrin. Proc. Nat. Acad. Sci. 87: 3117-3121, 1990.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/10/2011
*FIELD* CD
Carol A. Bocchini: 2/24/2009
*FIELD* ED
carol: 09/13/2013
wwang: 5/23/2011
ckniffin: 5/10/2011
terry: 2/26/2009
carol: 2/26/2009
*RECORD*
*FIELD* NO
612641
*FIELD* TI
*612641 ANKYRIN 1; ANK1
;;ANKYRIN, ERYTHROCYTIC
ANKYRIN-R, INCLUDED; ANK, INCLUDED;;
read moreANKYRIN 1 MUSCLE-SPECIFIC ISOFORM, INCLUDED
*FIELD* TX
CLONING
By analysis of cDNA for human erythroid ankyrin, Lux et al. (1990)
determined that the mature protein contains 1,880 amino acids comprising
an N-terminal domain binding integral membrane proteins and tubulin, a
central domain binding spectrin and vimentin, and an acidic C-terminal
'regulatory' domain containing an alternatively spliced sequence missing
from ankyrin variant 2.2. The N-terminal domain is composed almost
entirely of 22 tandem 33-amino acid repeats.
Lambert et al. (1990) found that the cDNA sequence has a large open
reading frame of 5,636 basepairs coding for a polypeptide of 1,879 amino
acids for the predicted molecular mass of 206 kD. Ankyrin comprises a
band-3 (SLC4A1; 109270)-binding domain, a spectrin-binding domain, and a
regulatory domain. The band-3-binding domain consists of 23 homologous
repeats, each 33 amino acids in length. The regulatory domain differs in
length in the 2 isoforms of ankyrin, proteins 2.1 and 2.2.
By Northern blot analysis of human skeletal muscle tissue with an
erythroid ANK1 probe, Gallagher and Forget (1998) detected expression of
2.3- and 1.6-kb transcripts, much smaller than the 7.3- and 9.0-kb
transcripts observed in erythroid tissue RNA. Using a 5-prime RACE
skeletal muscle product as probe, they identified a cDNA encoding a
155-amino acid protein. Secondary structure analysis predicted the
presence of a highly charged N-terminal domain followed by a C-terminal
domain composed of alternating alpha helix and beta sheet. The
membrane-binding domain, the spectrin/fodrin-binding domain, and most of
the regulatory domains found in the erythroid form of ANK1 are missing.
Genomic sequence analysis determined that the smaller transcript
contains 4 exons, a novel exon 1 followed by the erythroid exons 40, 41,
and 42, spread over approximately 10 kb. Exon 1 is located in intron 39
of the erythroid ANK gene. Northern blot analysis revealed abundant
expression of the 2.3- and 1.6-kb transcripts restricted to skeletal and
cardiac muscle with lesser amounts of 3.7- and 7.0-kb transcripts.
Immunoblot analysis showed that muscle ANK1 is readily detected as 28-
and 30-kD proteins in skeletal muscle but that detection of 70-kD and
210-kD proteins in erythrocyte membranes requires prolonged exposure.
GENE STRUCTURE
Tse et al. (1990) described the structure of the ANK1 gene corresponding
to the domain structure of the protein.
MAPPING
By fluorescence-based in situ hybridization, Tse et al. (1990) localized
the ankyrin gene to 8p11.2. Lux et al. (1990) independently reported
localization of ANK1 to chromosome 8p11.2 by FISH analysis.
MOLECULAR GENETICS
Davies and Lux (1989) stated that dosage analysis in 2 hereditary
spherocytosis patients with chromosome 8p11 deletions showed them to be
hemizygous for the ankyrin gene. A corresponding reduction of
approximately 50% in the amount of ankyrin protein was also seen in
these patients, who had mental retardation in addition to the red cell
defect. In both normoblastosis mice and hereditary spherocytosis humans,
spectrin is also reduced as a secondary phenomenon.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime
untranslated/promoter region of ankyrin-1 and the 19 coding exons of
band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They
identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense
mutations and a mutation in the putative ankyrin-1 promoter were common
in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3
frameshift and nonsense null mutations prevailed in dominant HS.
Increased accumulation of the normal protein product partially
compensated for the ankyrin-1 or band 3 defects in some of these null
mutations. The findings indicated to Eber et al. (1996) that ankyrin-1
mutations are a major cause of dominant and recessive HS (between 35 and
65%), that band 3 mutations are less common (between 15 and 25%), and
that the severity of HS is modified by factors other than the primary
gene defect.
In the proband reported by Duru et al. (1992), Edelman et al. (2007)
identified a homozygous splice site mutation in the ANK1 gene
(612641.0007). Each parent was heterozygous for the mutation.
ANIMAL MODEL
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb
locus maps to mouse chromosome 8 in a segment that shows homology of
synteny with human 8p (White and Barker, 1987). White et al. (1990) used
immunologic and biochemical methods to demonstrate an altered (150 kD)
immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+)
reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia,
significant neurologic dysfunction associated with Purkinje cell
degeneration in the cerebellum and the development of a late-onset
neurologic syndrome characterized by persistent tremor and gait
disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin
(HBG1; 142200) reporter gene in an erythroid-specific,
position-independent, copy number-dependent fashion in transgenic mice
to study spherocytosis-associated promoter mutations. They detected
abnormalities in reporter gene mRNA and protein expression. Mice with
the wildtype promoter demonstrated normal expression in all
erythrocytes, whereas mice with the -108T-C promoter mutation
(612641.0002) demonstrated varied expression. Undetectable or
significantly lower expression was found in mice with linked -108T-C and
-153G-A (612641.0006) promoter mutations. Gallagher et al. (2001)
concluded that functional defects can be caused by HS-related ankyrin
gene promoter mutations.
Salomao et al. (2010) found that glycophorin C (GPC; see 110750)
partitioning was unperturbed in nb/nb cells: GPC sorted to nascent
reticulocytes in both wildtype and nb/nb enucleating erythroblasts. In
addition, glycophorin A (GPA; see 111300), band 3 (SLC4A1; 109270), and
Rh antigen (RH; 111700) distributed predominantly to reticulocytes in
wildtype enucleating erythroblasts. However, band 3, GPA, and Rh antigen
sorted to both expelled nuclei and reticulocytes in nb/nb enucleating
erythroblasts. The findings demonstrated that, in mature nb/nb red
cells, a mechanism involving abnormal sorting during nuclear extrusion
results in multiple protein deficiencies. Salomao et al. (2010) also
raised the possibility that reticulocytes in hereditary spherocytosis
may differ from normal reticulocytes in their biophysical properties of
membrane cohesion or membrane deformability. The results also showed
that cytoskeletal attachments are an important factor in regulating
transmembrane protein sorting to reticulocytes.
*FIELD* AV
.0001
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN-RAKOVNIK
ANK1, GLU1669TER
In a kindred with autosomal dominant hereditary spherocytosis (182900),
Jarolim et al. (1995) identified a unique mutation in the regulatory
domain of ankyrin associated with a marked and selective deficiency of
ankyrin isoform 2.1 and a normal content of ankyrin isoform 2.2. The
deficiency of the 2.1 ankyrin isoform was accompanied by a proportional
deficiency of spectrin. The genetic defect was a nonsense mutation
glu1669-to-ter (GAA-to-TAA) in 1 allele of the ANK1 gene. Only normal
2.1 mRNA was detected in the reticulocyte RNA. The regulatory domain of
ankyrin is subject to extensive alternative splicing. In the case of
this mutation, alternative splicing within the regulatory domain of
ankyrin retained codon 1669 in ankyrin 2.1 mRNA and removed it from
ankyrin 2.2 mRNA. Jarolim et al. (1995) proposed that the glu1669-to-ter
mutation decreased the stability of the abnormal ankyrin 2.1 mRNA
allele, leading to a decreased synthesis of ankyrin 2.1 and a secondary
deficiency of spectrin. The mutant ankyrin was named for the city of
origin, Rakovnik, in the Czech Republic.
.0002
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, -108T-C
Eber et al. (1996) found that the ankyrin-1 promoter mutation, -108
T-to-C, is particularly common in recessive hereditary spherocytosis
(182900). The mutation lies immediately upstream of a first (minor)
transcription start site in the promoter region. They stated that
because the mutation is silent in heterozygotes, patients with recessive
HS must have a second mutation in the other allele. In 1 patient this
was a missense mutation, V463I, in the band-3-binding domain of
ankyrin-1. Notably, the patient's red cells were more deficient in band
3 than in ankyrin-1 or spectrin (182860), which is opposite to the trend
in other ankyrin-1 defects. The second mutation in another patient
created an amino acid change in a rare alternate splice product and
potentially a cryptic 5-prime splice site.
.0003
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN SAINT-ETIENNE 1
ANK1, TRP1721TER
In a kindred with autosomal dominant hereditary spherocytosis (182900),
Hayette et al. (1998) described a TGG-to-TGA transition in exon 39 of
the ANK1 gene resulting in a trp1721-to-ter stop mutation and truncation
of the ankyrin protein.
.0004
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN SAINT-ETIENNE 2
ANK1, ARG1833TER
In 2 families with autosomal dominant hereditary spherocytosis (182900),
Hayette et al. (1998) identified heterozygosity for an ANK1 truncating
mutation: codon 1833 in exon 41 was converted from CGA (arg) to TGA
(stop).
.0005
SPHEROCYTOSIS, TYPE 1, DUE TO ANKYRIN FLORIANOPOLIS
ANK1, 1-BP INS, 506C
In 3 unrelated probands from different ethnic backgrounds who had severe
hereditary spherocytosis (182900) requiring splenectomy, Gallagher et
al. (2000) found the same frameshift mutation in exon 4, insertion of an
extra cytosine nucleotide at codon 506 of the ANK1 gene. The patients
were of Italian, Portuguese, and German extraction and the mutation was
on a different haplotype in each.
.0006
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, -153G-A
Leite et al. (2000) identified a heterozygous G-to-A transition at
position -153 of the ANK1 promoter in a Brazilian kindred with
ankyrin-deficient recessive spherocytosis. The -153G-A mutation was
always found in cis with the -108C-T mutation (612641.0002), and these
linked mutations were silent in the heterozygous state.
.0007
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, IVS16AS, G-A, -17
In a Turkish boy with severe autosomal recessive spherocytosis (182900),
born of consanguineous parents, Edelman et al. (2007) identified a
homozygous G-to-A transition in intron 16 of the ANK1 gene
(IVS16AS-17G-A). The family had previously been reported by Duru et al.
(1992). Each parent, who had a milder form of spherocytosis, was
heterozygous for the mutation. Edelman et al. (2007) used denaturing
high-performance liquid chromatography (DHPLC) to identify the mutation.
RT-PCR of patient reticulocytes detected 9 abnormal splice isoforms of
ANK1 and no wildtype isoforms, indicating that the mutation interrupted
normal transcription.
.0008
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, 20-BP DEL, NT604
In a female German patient with moderate spherocytosis (182900), Eber et
al. (1996) identified a 20-bp deletion in exon 6 of the ANK1 gene,
resulting in frameshift and premature termination. Subsequently,
following reexamination of the patient, Gallagher et al. (2005)
identified compound heterozygosity for the 20-bp deletion and a 2-bp
deletion (-72delTG; 612641.0009) in the ANK1 promoter adjacent to a
transcription initiation site. Both parents had normal hematocrits,
increased reticulocyte counts, and abnormal erythrocyte incubated
osmotic fragility, typical for the diagnosis of HS with compensated
hemolysis. The mother carried the 20-bp deletion. The father was
presumed to carry the 2-bp deletion but was deceased, and there was no
genetic material available for testing. In vitro analysis of the mutant
promoter showed decreased levels of ANK1 expression, altered
transcription initiation site utilization and defective binding of
TATA-binding protein (TBP; 600075) and TFIID (TAF1; 313650) complex
formation. In a transgenic mouse model, the mutant ankyrin promoter led
to abnormalities in ANK1 expression, including decreased expression of a
reporter gene and altered transcription initiation site utilization. The
authors concluded that the promoter mutation altered ANK1 gene
transcription and contributes to the HS phenotype by decreasing ankyrin
gene synthesis via disruption of TFIID complex interactions with the
ankyrin core promoter. Gallagher et al. (2005) proposed that in
promoters that lack conserved cis elements, the TFIID complex may direct
preinitiation complex formation at specific sites in core promoter DNA.
.0009
SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE
ANK1, 2-BP DEL, -72TG
See 612641.0008 and Gallagher et al. (2005).
*FIELD* RF
1. Davies, K. A.; Lux, S. E.: Hereditary disorders of the red cell
membrane skeleton. Trends Genet. 5: 222-227, 1989.
2. Duru, F.; Gurgey, A.; Ozturk, G.; Yorukan, S.; Altay, C.: Homozygosity
for dominant form of hereditary spherocytosis. Brit. J. Haemat. 82:
596-600, 1992.
3. Eber, S. W.; Gonzalez, J. M.; Lux, M. L.; Scarpa, A. L.; Tse, W.
T.; Dornwell, M.; Herbers, J.; Kugler, W.; Ozcan, R.; Pekrun, A.;
Gallagher, P. G.; Schroter, W.; Forget, B. G.; Lux, S. E.: Ankyrin-1
mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature
Genet. 13: 214-218, 1996.
4. Edelman, E. J.; Maksimova, Y.; Duru, F.; Altay, C.; Gallagher,
P. G.: A complex splicing defect associated with homozygous ankyrin-deficient
hereditary spherocytosis. Blood 109: 5491-5493, 2007.
5. Gallagher, P. G.; Ferreira, J. D. S.; Costa, F. F.; Saad, S. T.
O.; Forget, B. G.: A recurrent frameshift mutation of the ankyrin
gene associated with severe hereditary spherocytosis. Brit. J. Haemat. 111:
1190-1193, 2000.
6. Gallagher, P. G.; Forget, B. G.: An alternate promoter directs
expression of a truncated, muscle-specific isoform of the human ankyrin
1 gene. J. Biol. Chem. 273: 1339-1348, 1998.
7. Gallagher, P. G.; Nilson, D. G.; Wong, C.; Weisbein, J. L.; Garrett-Beal,
L. J.; Eber, S. W.; Bodine, D. M.: A dinucleotide deletion in the
ankyrin promoter alters gene expression, transcription initiation
and TFIID complex formation in hereditary spherocytosis. Hum. Molec.
Genet. 14: 2501-2509, 2005.
8. Gallagher, P. G.; Sabatino, D. E.; Basseres, D. S.; Nilson, D.
M.; Wong, C.; Cline, A. P.; Garrett, L. J.; Bodine, D. M.: Erythrocyte
ankyrin promoter mutations associated with recessive hereditary spherocytosis
cause significant abnormalities in ankyrin expression. J. Biol. Chem. 276:
41683-41689, 2001.
9. Hayette, S.; Carre, G.; Bozon, M.; Alloisio, N.; Maillet, P.; Wilmotte,
R.; Pascal, O.; Reynaud, J.; Reman, O.; Stephan, J.-L.; Morle, L.;
Delaunay, J.: Two distinct truncated variants of ankyrin associated
with hereditary spherocytosis. Am. J. Hemat. 58: 36-41, 1998.
10. Jarolim, P.; Rubin, H. L.; Brabec, V.; Palek, J.: A nonsense
mutation glu1669-to-ter within the regulatory domain of human erythroid
ankyrin leads to a selective deficiency of the major ankyrin isoform
(band 2.1) and a phenotype of autosomal dominant hereditary spherocytosis. J.
Clin. Invest. 95: 941-947, 1995.
11. Lambert, S.; Yu, H.; Prchal, J. T.; Lawler, J.; Ruff, P.; Speicher,
D.; Cheung, M. C.; Kan, Y. W.; Palek, J.: cDNA sequence for human
erythrocyte ankyrin. Proc. Nat. Acad. Sci. 87: 1730-1734, 1990.
12. Leite, R. C. A.; Basseres, D. S.; Ferreira, J. S.; Alberto, F.
L.; Costa, F. F.; Saad, S. T. O.: Low frequency of ankyrin mutations
in hereditary spherocytosis: identification of three novel mutations. Hum.
Mutat. 16: 529 only, 2000.
13. Lux, S. E.; John, K. M.; Bennett, V.: Analysis of cDNA for human
erythrocyte ankyrin indicates a repeated structure with homology to
tissue-differentiation and cell-cycle control proteins. Nature 344:
36-42, 1990.
14. Peters, L. L.; Birkenmeier, C. S.; Bronson, R. T.; White, R. A.;
Lux, S. E.; Otto, E.; Bennett, V.; Higgins, A.; Barker, J. E.: Purkinje
cell degeneration associated with erythroid ankyrin deficiency in
nb/nb mice. J. Cell Biol. 114: 1233-1241, 1991.
15. Salomao, M.; Chen, K.; Villalobos, J.; Mohandas, N.; An, X.; Chasis,
J. A.: Hereditary spherocytosis and hereditary elliptocytosis: aberrant
protein sorting during erythroblast enucleation. Blood 116: 267-269,
2010.
16. Tse, W. T.; Meninger, J.; Ward, D.; John, K.; Lux, S. E.; Forget,
B. G.: Genomic cloning and chromosomal sublocalization of the human
ankyrin gene.(Abstract) Clin. Res. 38: 266A, 1990.
17. White, R.; Barker, J.: Normoblastosis, a mutant mouse with severe
hemolytic anemia.(Abstract) Blood 70S: 57a, 1987.
18. White, R. A.; Birkenmeier, C. S.; Lux, S. E.; Barker, J. E.:
Ankyrin and the hemolytic anemia mutation, nb, map to mouse chromosome
8: presence of the nb allele is associated with a truncated erythrocyte
ankyrin. Proc. Nat. Acad. Sci. 87: 3117-3121, 1990.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/10/2011
*FIELD* CD
Carol A. Bocchini: 2/24/2009
*FIELD* ED
carol: 09/13/2013
wwang: 5/23/2011
ckniffin: 5/10/2011
terry: 2/26/2009
carol: 2/26/2009