RBCC Red Blood Cell Collection

SPTB (SPTB1) [Confidence: high (present in two of the MS resources)]
Spectrin beta chain, erythrocytic (Beta-I spectrin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00004501
IPI00004501 & 216513(52) Splice isoform 1 2 of P11277 Spectrin beta chain, erythrocyte Splice isoform 1 2 of P11277 Spectrin beta chain, erythrocyte membrane 36 12 143 112 147 71 135 98 232 18 93 87 21 71 49 25 66 139 119 11 cytoskeleton n/a found at its expected molecular weight found at molecular weight

UniProt P11277
ID SPTB1_HUMAN Reviewed; 2137 AA.
AC P11277; Q15510; Q15519;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 5.
DT 22-JAN-2014, entry version 154.
DE RecName: Full=Spectrin beta chain, erythrocytic;
DE AltName: Full=Beta-I spectrin;
GN Name=SPTB; Synonyms=SPTB1;
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 1 AND 3), AND VARIANTS ASN-439
RP AND ASP-1151.
RX PubMed=2195026;
RA Winkelmann J.C., Chang J.G., Tse W.T., Scarpa A.L., Marchesi V.T.,
RA Forget B.G.;
RT "Full-length sequence of the cDNA for human erythroid beta-spectrin.";
RL J. Biol. Chem. 265:11827-11832(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [3]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND ALTERNATIVE
RP SPLICING.
RX PubMed=2056132; DOI=10.1172/JCI115307;
RA Garbarz M., Tse W.T., Gallagher P.G., Picat C., Lecomte M.C.,
RA Galibert F., Dhermy D., Forget B.G.;
RT "Spectrin Rouen (beta 220-218), a novel shortened beta-chain variant
RT in a kindred with hereditary elliptocytosis. Characterization of the
RT molecular defect as exon skipping due to a splice site mutation.";
RL J. Clin. Invest. 88:76-81(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1055-2137 (ISOFORM 2), AND VARIANT
RP ASP-1151.
RC TISSUE=Skeletal muscle;
RX PubMed=2243099;
RA Winkelmann J.C., Costa F.F., Linzie B.L., Forget B.G.;
RT "Beta spectrin in human skeletal muscle. Tissue-specific differential
RT processing of 3' beta spectrin pre-mRNA generates a beta spectrin
RT isoform with a unique carboxyl terminus.";
RL J. Biol. Chem. 265:20449-20454(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2002-2137 (ISOFORM 1).
RX PubMed=1840591;
RA Gallagher P.G., Tse W.T., Costa F., Scarpa A., Boivin P., Delaunay J.,
RA Forget B.G.;
RT "A splice site mutation of the beta-spectrin gene causing exon
RT skipping in hereditary elliptocytosis associated with a truncated
RT beta-spectrin chain.";
RL J. Biol. Chem. 266:15154-15159(1991).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 928-1756 (ISOFORMS 1/2/3), AND VARIANT
RP ASP-1151.
RX PubMed=1976574; DOI=10.1016/0378-1119(90)90104-Y;
RA Yoon S.H., Kentros C.G., Prchal J.T.;
RT "Identification of an unusual deletion within homologous repeats of
RT human reticulocyte beta-spectrin and probable peptide polymorphism.";
RL Gene 91:297-302(1990).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1334-1432 (ISOFORMS 1/2/3), NUCLEOTIDE
RP SEQUENCE [MRNA] OF 1909-2137 (ISOFORM 1), AND VARIANT ARG-1374.
RX PubMed=3390609;
RA Winkelmann J.C., Leto T.L., Watkins P.C., Eddy R., Shows T.B.,
RA Linnenbach A.J., Sahr K.E., Kathuria N., Marchesi V.T., Forget B.G.;
RT "Molecular cloning of the cDNA for human erythrocyte beta-spectrin.";
RL Blood 72:328-334(1988).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1209-1482 (ISOFORMS 1/2/3).
RX PubMed=3478706; DOI=10.1073/pnas.84.21.7468;
RA Prchal J.T., Morley B.J., Yoon S.-H., Coetzer T.L., Palek J.,
RA Conboy J.G., Kan Y.W.;
RT "Isolation and characterization of cDNA clones for human erythrocyte
RT beta-spectrin.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:7468-7472(1987).
RN [9]
RP PROTEIN SEQUENCE OF 2-18.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [10]
RP DOMAINS.
RX PubMed=6472478; DOI=10.1038/311177a0;
RA Speicher D.W., Marchesi V.T.;
RT "Erythrocyte spectrin is comprised of many homologous triple helical
RT segments.";
RL Nature 311:177-180(1984).
RN [11]
RP PHOSPHORYLATION AT THR-2110; SER-2114; SER-2117; SER-2123; SER-2125
RP AND SER-2128.
RX PubMed=15065869; DOI=10.1021/bi036092x;
RA Tang H.Y., Speicher D.W.;
RT "In vivo phosphorylation of human erythrocyte spectrin occurs in a
RT sequential manner.";
RL Biochemistry 43:4251-4262(2004).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1064-1275.
RX PubMed=15062087; DOI=10.1016/j.str.2004.02.022;
RA Kusunoki H., MacDonald R.I., Mondragon A.;
RT "Structural insights into the stability and flexibility of unusual
RT erythroid spectrin repeats.";
RL Structure 12:645-656(2004).
RN [14]
RP REVIEW ON VARIANTS.
RX PubMed=8844207;
RX DOI=10.1002/(SICI)1098-1004(1996)8:2<97::AID-HUMU1>3.3.CO;2-W;
RA Maillet P., Alloisio N., Morle L., Delaunay J.;
RT "Spectrin mutations in hereditary elliptocytosis and hereditary
RT spherocytosis.";
RL Hum. Mutat. 8:97-107(1996).
RN [15]
RP VARIANT EL3 CAGLIARI GLY-2018.
RX PubMed=8226774;
RA Sahr K.E., Coetzer T.L., Moy L.S., Derick L.H., Chishti A.H.,
RA Jarolim P., Lorenzo F., del Giudice E.M., Iolascon A., Gallanello R.,
RA Cao A., Delaunay J., Liu S.-C., Palek J.;
RT "Spectrin Cagliari: an Ala-->Gly substitution in helix 1 of beta
RT spectrin repeat 17 that severely disrupts the structure and self-
RT association of the erythrocyte spectrin heterodimer.";
RL J. Biol. Chem. 268:22656-22662(1993).
RN [16]
RP VARIANT HS KISSIMMEE ARG-202.
RX PubMed=8102379; DOI=10.1172/JCI116628;
RA Becker P.S., Tse W.T., Lux S.E., Forget B.G.;
RT "Beta spectrin Kissimmee: a spectrin variant associated with autosomal
RT dominant hereditary spherocytosis and defective binding to protein
RT 4.1.";
RL J. Clin. Invest. 92:612-616(1993).
RN [17]
RP VARIANT EL3 PROVIDENCE PRO-2019.
RX PubMed=7883966; DOI=10.1172/JCI117766;
RA Gallagher P.G., Weed S.A., Tse W.T., Benoit L., Morrow J.S.,
RA Marchesi S.L., Mohandas N., Forget B.G.;
RT "Recurrent fatal hydrops fetalis associated with a nucleotide
RT substitution in the erythrocyte beta-spectrin gene.";
RL J. Clin. Invest. 95:1174-1182(1995).
RN [18]
RP VARIANTS EL3 VAL-2023 AND ARG-2024.
RX PubMed=8018926;
RA Parquet N., Devaux I., Boulanger L., Galand C., Boivin P.,
RA Lecomte M.-C., Dhermy D., Garbarz M.;
RT "Identification of three novel spectrin alpha I/74 mutations in
RT hereditary elliptocytosis: further support for a triple-stranded
RT folding unit model of the spectrin heterodimer contact site.";
RL Blood 84:303-308(1994).
RN [19]
RP VARIANT EL3 PRO-2053.
RX PubMed=1975598; DOI=10.1172/JCI114792;
RA Tse W.T., Lecomte M.-C., Costa F.F., Garbarz M., Feo C., Boivin P.,
RA Dhermy D., Forget B.G.;
RT "Point mutation in the beta-spectrin gene associated with alpha I/74
RT hereditary elliptocytosis. Implications for the mechanism of spectrin
RT dimer self-association.";
RL J. Clin. Invest. 86:909-916(1990).
CC -!- FUNCTION: Spectrin is the major constituent of the cytoskeletal
CC network underlying the erythrocyte plasma membrane. It associates
CC with band 4.1 and actin to form the cytoskeletal superstructure of
CC the erythrocyte plasma membrane.
CC -!- SUBUNIT: Composed of nonhomologous chains, alpha and beta, which
CC aggregate to form dimers, tetramers, and higher polymers.
CC -!- INTERACTION:
CC O95295:SNAPIN; NbExp=3; IntAct=EBI-514908, EBI-296723;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm, cell
CC cortex.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P11277-1; Sequence=Displayed;
CC Name=2; Synonyms=Muscle-specific;
CC IsoId=P11277-2; Sequence=VSP_000719;
CC Name=3;
CC IsoId=P11277-3; Sequence=VSP_007242;
CC Note=Due to exon skipping;
CC -!- PTM: The first phosphorylation event occurs on Ser-2114, followed
CC by Ser-2125, Ser-2123, Ser-2128, Ser-2117, and Thr-2110.
CC -!- DISEASE: Elliptocytosis 3 (EL3) [MIM:182870]: A Rhesus-unlinked
CC form of hereditary elliptocytosis, a genetically heterogeneous,
CC autosomal dominant hematologic disorder. It is characterized by
CC variable hemolytic anemia and elliptical or oval red cell shape.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Spherocytosis 2 (SPH2) [MIM:182870]: 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 dominant. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: This complex is anchored to the cytoplasmic face of
CC the plasma membrane via another protein, ankyrin, which binds to
CC beta-spectrin and mediates the binding of the whole complex to a
CC transmembrane protein band 3. The interaction of erythrocyte
CC spectrin with other proteins through specific binding domains lead
CC to the formation of an extensive subplasmalemmal meshwork which is
CC thought to be responsible for the maintenance of the biconcave
CC shape of human erythrocytes, for the regulation of plasma membrane
CC components and for the maintenance of the lipid asymmetry of the
CC plasma membrane.
CC -!- SIMILARITY: Belongs to the spectrin family.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 17 spectrin repeats.
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DR EMBL; J05500; AAA60578.1; -; mRNA.
DR EMBL; J05500; AAA60579.1; -; mRNA.
DR EMBL; AL121774; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M37884; AAA63259.1; -; mRNA.
DR EMBL; M37885; AAA60571.1; -; mRNA.
DR EMBL; M57948; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X59510; CAA42097.1; -; mRNA.
DR EMBL; X59511; CAA42098.1; -; mRNA.
DR EMBL; M18054; AAA60572.1; -; mRNA.
DR PIR; A37064; SJHUB.
DR RefSeq; NP_000338.3; NM_000347.5.
DR RefSeq; NP_001020029.1; NM_001024858.2.
DR RefSeq; XP_005268080.1; XM_005268023.1.
DR UniGene; Hs.417303; -.
DR PDB; 1S35; X-ray; 2.40 A; A=1064-1275.
DR PDB; 3EDU; X-ray; 2.10 A; A=1692-1907.
DR PDB; 3F57; X-ray; 2.90 A; A/B=1686-1907.
DR PDB; 3KBT; X-ray; 2.75 A; A/B=1583-1906.
DR PDB; 3KBU; X-ray; 2.75 A; A/B=1583-1906.
DR PDB; 3LBX; X-ray; 2.80 A; B=1902-2084.
DR PDBsum; 1S35; -.
DR PDBsum; 3EDU; -.
DR PDBsum; 3F57; -.
DR PDBsum; 3KBT; -.
DR PDBsum; 3KBU; -.
DR PDBsum; 3LBX; -.
DR ProteinModelPortal; P11277; -.
DR SMR; P11277; 48-280, 299-2083.
DR DIP; DIP-1021N; -.
DR IntAct; P11277; 6.
DR MINT; MINT-3007632; -.
DR STRING; 9606.ENSP00000374372; -.
DR PhosphoSite; P11277; -.
DR DMDM; 215274269; -.
DR SWISS-2DPAGE; P11277; -.
DR PaxDb; P11277; -.
DR PRIDE; P11277; -.
DR Ensembl; ENST00000389720; ENSP00000374370; ENSG00000070182.
DR Ensembl; ENST00000389721; ENSP00000374371; ENSG00000070182.
DR Ensembl; ENST00000389722; ENSP00000374372; ENSG00000070182.
DR Ensembl; ENST00000542895; ENSP00000443882; ENSG00000070182.
DR Ensembl; ENST00000556626; ENSP00000451752; ENSG00000070182.
DR GeneID; 6710; -.
DR KEGG; hsa:6710; -.
DR UCSC; uc001xht.3; human.
DR CTD; 6710; -.
DR GeneCards; GC14M065213; -.
DR HGNC; HGNC:11274; SPTB.
DR HPA; CAB015169; -.
DR HPA; HPA003394; -.
DR HPA; HPA003398; -.
DR MIM; 130600; phenotype.
DR MIM; 182870; gene+phenotype.
DR neXtProt; NX_P11277; -.
DR Orphanet; 98864; Common hereditary elliptocytosis.
DR Orphanet; 98867; Hereditary pyropoikilocytosis.
DR Orphanet; 822; Hereditary spherocytosis.
DR Orphanet; 98866; Spherocytic elliptocytosis.
DR PharmGKB; PA36103; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000007281; -.
DR HOVERGEN; HBG057912; -.
DR KO; K06115; -.
DR OMA; ESFHRVH; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_127416; Developmental Biology.
DR EvolutionaryTrace; P11277; -.
DR GeneWiki; SPTB; -.
DR GenomeRNAi; 6710; -.
DR NextBio; 26166; -.
DR PRO; PR:P11277; -.
DR ArrayExpress; P11277; -.
DR Bgee; P11277; -.
DR CleanEx; HS_SPTB; -.
DR Genevestigator; P11277; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031235; C:intrinsic to cytoplasmic side of plasma membrane; TAS:BHF-UCL.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0008091; C:spectrin; TAS:ProtInc.
DR GO; GO:0014731; C:spectrin-associated cytoskeleton; IDA:BHF-UCL.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; IEA:InterPro.
DR GO; GO:0051693; P:actin filament capping; IEA:UniProtKB-KW.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0030097; P:hemopoiesis; IEA:Ensembl.
DR GO; GO:0007009; P:plasma membrane organization; IEA:Ensembl.
DR GO; GO:0006779; P:porphyrin-containing compound biosynthetic process; IEA:Ensembl.
DR Gene3D; 1.10.418.10; -; 2.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR016343; Spectrin_bsu.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF00435; Spectrin; 17.
DR PIRSF; PIRSF002297; Spectrin_beta_subunit; 1.
DR SMART; SM00033; CH; 2.
DR SMART; SM00150; SPEC; 17.
DR SUPFAM; SSF47576; SSF47576; 1.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Actin capping; Actin-binding; Alternative splicing;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease mutation; Elliptocytosis; Hereditary hemolytic anemia;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 2137 Spectrin beta chain, erythrocytic.
FT /FTId=PRO_0000073459.
FT DOMAIN 2 275 Actin-binding.
FT DOMAIN 54 158 CH 1.
FT DOMAIN 173 275 CH 2.
FT REPEAT 276 384 Spectrin 1.
FT REPEAT 385 498 Spectrin 2.
FT REPEAT 499 607 Spectrin 3.
FT REPEAT 608 713 Spectrin 4.
FT REPEAT 714 818 Spectrin 5.
FT REPEAT 819 924 Spectrin 6.
FT REPEAT 925 1031 Spectrin 7.
FT REPEAT 1032 1138 Spectrin 8.
FT REPEAT 1139 1244 Spectrin 9.
FT REPEAT 1245 1349 Spectrin 10.
FT REPEAT 1350 1455 Spectrin 11.
FT REPEAT 1456 1554 Spectrin 12.
FT REPEAT 1555 1660 Spectrin 13.
FT REPEAT 1661 1767 Spectrin 14.
FT REPEAT 1768 1873 Spectrin 15.
FT REPEAT 1874 1979 Spectrin 16.
FT REPEAT 1980 2085 Spectrin 17.
FT MOD_RES 2110 2110 Phosphothreonine.
FT MOD_RES 2114 2114 Phosphoserine.
FT MOD_RES 2117 2117 Phosphoserine.
FT MOD_RES 2123 2123 Phosphoserine.
FT MOD_RES 2125 2125 Phosphoserine.
FT MOD_RES 2128 2128 Phosphoserine.
FT VAR_SEQ 2074 2137 LELKERQIAERPAEETGPQEEEGETAGEAPVSHHAATERTS
FT PVSLWSRLSSSWESLQPEPSHPY -> ASRGGRRDSRGGSS
FT FPPCGHRENVPGQSLVSFV (in isoform 3).
FT /FTId=VSP_007242.
FT VAR_SEQ 2116 2137 VSLWSRLSSSWESLQPEPSHPY -> GEEEGTWPQNLQQPP
FT PPGQHKDGQKSTGDERPTTEPLFKVLDTPLSEGDEPATLPA
FT PRDHGQSVQMEGYLGRKHDLEGPNKKASNRSWNNLYCVLRN
FT SELTFYKDAKNLALGMPYHGEEPLALRHAICEIAANYKKKK
FT HVFKLRLSNGSEWLFHGKDEEEMLSWLQGVSTAINESQSIR
FT VKAQSLPLPSLSGPDASLGKKDKEKRFSFFPKKK (in
FT isoform 2).
FT /FTId=VSP_000719.
FT VARIANT 202 202 W -> R (in HS; Kissimmee).
FT /FTId=VAR_001352.
FT VARIANT 439 439 S -> N (in dbSNP:rs229587).
FT /FTId=VAR_001353.
FT VARIANT 525 525 E -> K (in dbSNP:rs55752508).
FT /FTId=VAR_061084.
FT VARIANT 613 613 S -> I (in dbSNP:rs3742601).
FT /FTId=VAR_038514.
FT VARIANT 1151 1151 N -> D (in dbSNP:rs77806).
FT /FTId=VAR_001354.
FT VARIANT 1374 1374 H -> R (in dbSNP:rs10132778).
FT /FTId=VAR_001355.
FT VARIANT 1403 1403 R -> Q (in dbSNP:rs17180350).
FT /FTId=VAR_001356.
FT VARIANT 1408 1408 G -> R (in dbSNP:rs17245552).
FT /FTId=VAR_038515.
FT VARIANT 2018 2018 A -> G (in EL3; Cagliary).
FT /FTId=VAR_001357.
FT VARIANT 2019 2019 S -> P (in EL3; Providence).
FT /FTId=VAR_001358.
FT VARIANT 2023 2023 A -> V (in EL3; Paris).
FT /FTId=VAR_001359.
FT VARIANT 2024 2024 W -> R (in EL3; Linguere).
FT /FTId=VAR_001360.
FT VARIANT 2025 2025 L -> R (in EL3; Buffalo).
FT /FTId=VAR_001361.
FT VARIANT 2053 2053 A -> P (in EL3; Kayes).
FT /FTId=VAR_001362.
FT CONFLICT 403 403 E -> G (in Ref. 1; AAA60578/AAA60579).
FT CONFLICT 612 612 I -> M (in Ref. 1; AAA60578/AAA60579).
FT CONFLICT 629 631 RKA -> ART (in Ref. 1; AAA60578/
FT AAA60579).
FT CONFLICT 958 959 NY -> TL (in Ref. 1; AAA60578/AAA60579).
FT CONFLICT 1031 1031 D -> N (in Ref. 1; AAA60578/AAA60579).
FT CONFLICT 1844 1845 EL -> DV (in Ref. 1; AAA60578/AAA60579
FT and 3; AAA63259).
FT HELIX 1065 1085
FT HELIX 1093 1128
FT HELIX 1134 1192
FT HELIX 1200 1236
FT HELIX 1242 1271
FT HELIX 1586 1605
FT HELIX 1616 1652
FT HELIX 1692 1713
FT HELIX 1722 1759
FT HELIX 1765 1818
FT HELIX 1838 1863
FT HELIX 1868 1891
FT HELIX 1902 1928
FT STRAND 1936 1938
FT HELIX 1941 1971
FT HELIX 1977 2033
FT HELIX 2041 2060
FT HELIX 2062 2069
FT HELIX 2073 2082
SQ SEQUENCE 2137 AA; 246468 MW; 311AE5CD53237610 CRC64;
MTSATEFENV GNQPPYSRIN ARWDAPDDEL DNDNSSARLF ERSRIKALAD EREVVQKKTF
TKWVNSHLAR VSCRITDLYK DLRDGRMLIK LLEVLSGEML PKPTKGKMRI HCLENVDKAL
QFLKEQRVHL ENMGSHDIVD GNHRLVLGLI WTIILRFQIQ DIVVQTQEGR ETRSAKDALL
LWCQMKTAGY PHVNVTNFTS SWKDGLAFNA LIHKHRPDLI DFDKLKDSNA RHNLEHAFNV
AERQLGIIPL LDPEDVFTEN PDEKSIITYV VAFYHYFSKM KVLAVEGKRV GKVIDHAIET
EKMIEKYSGL ASDLLTWIEQ TITVLNSRKF ANSLTGVQQQ LQAFSTYRTV EKPPKFQEKG
NLEVLLFTIQ SRMRANNQKV YTPHDGKLVS DINRAWESLE EAEYRRELAL RNELIRQEKL
EQLARRFDRK AAMRETWLSE NQRLVAQDNF GYDLAAVEAA KKKHEAIETD TAAYEERVRA
LEDLAQELEK ENYHDQKRIT ARKDNILRLW SYLQELLQSR RQRLETTLAL QKLFQDMLHS
IDWMDEIKAH LLSAEFGKHL LEVEDLLQKH KLMEADIAIQ GDKVKAITAA TLKFTEGKGY
QPCDPQVIQD RISHLEQCFE ELSNMAAGRK AQLEQSKRLW KFFWEMDEAE SWIKEKEQIY
SSLDYGKDLT SVLILQRKHK AFEDELRGLD AHLEQIFQEA HGMVARKQFG HPQIEARIKE
VSAQWDQLKD LAAFCKKNLQ DAENFFQFQG DADDLKAWLQ DAHRLLSGED VGQDEGATRA
LGKKHKDFLE ELEESRGVME HLEQQAQGFP EEFRDSPDVT HRLQALRELY QQVVAQADLR
QQRLQEALDL YTVFGETDAC ELWMGEKEKW LAEMEMPDTL EDLEVVQHRF DILDQEMKTL
MTQIDGVNLA ANSLVESGHP RSREVKQYQD HLNTRWQAFQ TLVSERREAV DSALRVHNYC
VDCEETSKWI TDKTKVVEST KDLGRDLAGI IAIQRKLSGL ERDVAAIQAR VDALERESQQ
LMDSHPEQKE DIGQRQKHLE ELWQGLQQSL QGQEDLLGEV SQLQAFLQDL DDFQAWLSIT
QKAVASEDMP ESLPEAEQLL QQHAGIKDEI DGHQDSYQRV KESGEKVIQG QTDPEYLLLG
QRLEGLDTGW NALGRMWESR SHTLAQCLGF QEFQKDAKQA EAILSNQEYT LAHLEPPDSL
EAAEAGIRKF EDFLGSMENN RDKVLSPVDS GNKLVAEGNL YSDKIKEKVQ LIEDRHRKNN
EKAQEASVLL RDNLELQNFL QNCQELTLWI NDKLLTSQDV SYDEARNLHN KWLKHQAFVA
ELASHEGWLE NIDAEGKQLM DEKPQFTALV SQKLEALHRL WDELQATTKE KTQHLSAARS
SDLRLQTHAD LNKWISAMED QLRSDDPGKD LTSVNRMLAK LKRVEDQVNV RKEELGELFA
QVPSMGEEGG DADLSIEKRF LDLLEPLGRR KKQLESSRAK LQISRDLEDE TLWVEERLPL
AQSADYGTNL QTVQLFMKKN QTLQNEILGH TPRVEDVLQR GQQLVEAAEI DCQDLEERLG
HLQSSWDRLR EAAAGRLQRL RDANEAQQYY LDADEAEAWI GEQELYVISD EIPKDEEGAI
VMLKRHLRQQ RAVEDYGRNI KQLASRAQGL LSAGHPEGEQ IIRLQGQVDK HYAGLKDVAE
ERKRKLENMY HLFQLKRETD DLEQWISEKE LVASSPEMGQ DFDHVTLLRD KFRDFARETG
AIGQERVDNV NAFIERLIDA GHSEAATIAE WKDGLNEMWA DLLELIDTRM QLLAASYDLH
RYFYTGAEIL GLIDEKHREL PEDVGLDAST AESFHRVHTA FERELHLLGV QVQQFQDVAT
RLQTAYAGEK AEAIQNKEQE VSAAWQALLD ACAGRRTQLV DTADKFRFFS MARDLLSWME
SIIRQIETQE RPRDVSSVEL LMKYHQGINA EIETRSKNFS ACLELGESLL QRQHQASEEI
REKLQQVMSR RKEMNEKWEA RWERLRMLLE VCQFSRDASV AEAWLIAQEP YLASGDFGHT
VDSVEKLIKR HEAFEKSTAS WAERFAALEK PTTLELKERQ IAERPAEETG PQEEEGETAG
EAPVSHHAAT ERTSPVSLWS RLSSSWESLQ PEPSHPY
//

MIM 130600
*RECORD*
*FIELD* NO
130600
*FIELD* TI
#130600 ELLIPTOCYTOSIS 2; EL2
;;ELLIPTOCYTOSIS, RHESUS-UNLINKED TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreelliptocytosis-2 is caused by heterozygous mutation in the
alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23.

For a general description and a discussion of genetic heterogeneity of
elliptocytosis (HE), see EL1 (611804).

CLINICAL FEATURES

In some families with HE, spectrin is abnormally heat-sensitive (Lux and
Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of
hereditary elliptocytosis and found an abnormality of tryptic digestion
in 1. This patient was previously reported by Gomperts et al. (1973) as
an instance of hemolytic anemia due to HE.

Liu et al. (1982) examined erythrocytes from 18 patients with hereditary
elliptocytosis. In 8 patients (referred to as type 1), spectrin was
defective in dimer-dimer association as demonstrated in 2 ways. First,
spectrin dimer was increased and tetramer decreased; spectrin dimer
represented 15 to 33% of total spectrin compared with a normal range of
3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer
association was decreased in both solution and in situ in red cell
membranes. In the other 10 patients (referred to as type 2), dimer-dimer
association was normal. Membrane skeletons, produced from both types of
elliptocytosis by Triton X-100 extraction of the red cell ghosts, were
unstable when mechanically shaken. Spectrin tetramers but not dimers can
crosslink actin.

Evans et al. (1983) studied a family in which 3 sibs had severe
transfusion-dependent, presumably homozygous elliptocytosis and both
parents had asymptomatic elliptocytosis. Red cell membranes of all 3
sibs showed an excess of spectrin dimers over tetramers in spectrin
extracts. Both parents showed an intermediate increase in spectrin
dimers.

In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et
al. (1985) found an abnormal thermal sensitivity and an important defect
of spectrin dimer self-association. An excess of spectrin dimer and
deficient dimer-to-tetramer conversion were demonstrated. Peptide
patterns of crude spectrin showed a marked decrease in the 80-kD peptide
(previously identified as the dimer-dimer interaction domain of the
alpha chain) and a concomitant appearance of a novel 65-kD peptide.
Anti-alpha-spectrin antibodies showed that the latter peptide was
derived from the alpha chain. The patients were 3 unrelated adults, 2
children with hemolytic anemia, and the father of each child.

Lawler et al. (1984, 1985) described a molecular defect in the alpha
subunit of spectrin in a subset of patients with hereditary
elliptocytosis; the self-association of alpha-beta heterodimers to form
tetramers was defective.

Abnormality of alpha spectrin was reported by Ravindranath and Johnson
(1985) in a case of congenital hemolytic anemia.

Lambert and Zail (1987) also found a variant of the alpha subunit. Two
brothers with the poikilocytic variant of hereditary elliptocytosis were
found to have a defect in spectrin dimer association and a decreased
spectrin/band 3 ratio. The major abnormal tryptic peptides derived from
the alpha-I domain had lower molecular weights and more basic
isoelectric points than hitherto described. The propositus of Lambert
and Zail (1987) was a black South African miner.

In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic
anemia with red cell fragmentation, poikilocytosis, and elliptocytosis.
Both parents and a brother of the propositus had compensated mild
hereditary elliptocytosis. Studies indicated that the proband was
homozygous for an alpha-I/65 spectrin variant whereas both parents were
heterozygous.

In a family with hereditary elliptocytosis, Lane et al. (1987) found
that alpha-spectrin subunits migrated anomalously in SDS-PAGE. The
quantity of the alpha-spectrin mutant, expressed as a percentage of the
total alpha spectrin, varied from 9.9 to 45.2% among 6 affected persons.
Other findings suggested that this new alpha-spectrin mutant is
responsible for decreased spectrin dimer-dimer association and for red
cell instability. The propositus, a 23-month-old boy, exhibited anemia,
hyperbilirubinemia requiring phototherapy, and striking red cell
poikilocytosis at birth. His only sib, a 4-year-old who had
hyperbilirubinemia at birth, exhibited elliptocytosis without
poikilocytosis at the time of study. The mother, 2 of her sibs, and the
maternal grandfather had elliptocytosis.

MAPPING

Morton (1956) defined the existence of Rh-linked (611804) and
Rh-unlinked forms of elliptocytosis and emphasized the usefulness of
linkage studies in demonstration of genetic heterogeneity.

Keats (1979) suggested that a second elliptocytosis locus unlinked to Rh
is on chromosome 1. She found a lod score of 1.97 for theta of 0.0 for
linkage with Duffy. From analysis of the data by a maximum likelihood
method, Rao et al. (1979) concluded that there is 'nonsignificant
evidence of linkage' of an Rh-unlinked form of elliptocytosis to
chromosome 1 (lod score, 2.08).

MOLECULAR GENETICS

By in situ hybridization, the SPTA1 gene was mapped to 1q22-1q25
(Huebner et al., 1985) in the region proposed by Keats (1979) for a
non-Rh-linked form of elliptocytosis. In patients with elliptocytosis,
Marchesi et al. (1987) identified heterozygous mutations in the SPTA1
gene (182860.0001-182860.0002). This is one of the first examples of
positive results from the 'candidate gene' approach to elucidating
etiopathogenesis.

*FIELD* SA
Lux et al. (1981)
*FIELD* RF
1. Coetzer, T.; Zail, S. S.: Tryptic digestion of spectrin in variants
of hereditary elliptocytosis. J. Clin. Invest. 67: 1241-1248, 1981.

2. Evans, J. P. M.; Baines, A. J.; Hann, I. M.; Al-Hakim, I.; Knowles,
S. M.; Hoffbrand, A. V.: Defective spectrin dimer-dimer association
in a family with transfusion dependent homozygous hereditary elliptocytosis. Brit.
J. Haemat. 54: 163-172, 1983.

3. Garbarz, M.; Lecomte, M. C.; Dhermy, D.; Feo, C.; Chaveroche, I.;
Gautero, H.; Bournier, O.; Picat, C.; Goepp, A.; Boivin, P.: Double
inheritance of an alpha I/65 spectrin variant in a child with homozygous
elliptocytosis. Blood 67: 1661-1667, 1986.

4. Gomperts, E. D.; Cayannis, F.; Metz, J.; Zail, S. S.: A red cell
membrane protein abnormality in hereditary elliptocytosis. Brit.
J. Haemat. 25: 415-420, 1973.

5. Huebner, K.; Palumbo, A. P.; Isobe, M.; Kozak, C. A.; Monaco, S.;
Rovera, G.; Croce, C. M.; Curtis, P. J.: The alpha-spectrin gene
is on chromosome 1 in mouse and man. Proc. Nat. Acad. Sci. 82: 3790-3793,
1985.

6. Keats, B. J. B.: Another elliptocytosis locus on chromosome 1? Hum.
Genet. 50: 227-230, 1979.

7. Lambert, S.; Zail, S.: A new variant of the alpha-subunit of spectrin
in hereditary elliptocytosis. Blood 69: 473-478, 1987.

8. Lane, P. A.; Shew, R. L.; Iarocci, T. A.; Mohandas, N.; Hays, T.;
Mentzer, W. C.: Unique alpha-spectrin mutant in a kindred with common
hereditary elliptocytosis. J. Clin. Invest. 79: 989-996, 1987.

9. Lawler, J.; Coetzer, T. L.; Palek, J.; Jacob, H. S.; Luban, N.
: Sp alpha(I/65): a new variant of the alpha subunit of spectrin in
hereditary elliptocytosis. Blood 66: 706-709, 1985.

10. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: A molecular defect
in spectrin with a subset of patients with hereditary elliptocytosis:
alterations in the alpha-subunit domain involved in spectrin self-association. J.
Clin. Invest. 73: 1688-1695, 1984.

11. Lecomte, M.-C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
Bournier, O.; Picat, C.; Chaveroche, I.; Ester, A.; Galand, C.; Boivin,
P.: Pathologic and nonpathologic variants of the spectrin molecule
in two black families with hereditary elliptocytosis. Hum. Genet. 71:
351-357, 1985.

12. Liu, S.-C.; Palek, J.; Prchal, J. T.: Defective spectrin dimer-dimer
association in hereditary elliptocytosis. Proc. Nat. Acad. Sci. 79:
2072-2076, 1982.

13. Lux, S. E.; Wolfe, L. C.: Inherited disorders of the red cell
membrane skeleton. Pediat. Clin. N. Am. 27: 463-486, 1980.

14. Lux, S. E.; Wolfe, L. C.; Pease, B.; Tomaselli, M. B.; John, K.
M.; Bernstein, S. E.: Hemolytic anemias due to abnormalities of red
cell spectrin: a brief review. Prog. Clin. Biol. Res. 45: 159-168,
1981.

15. Marchesi, S. L.; Letsinger, J. T.; Speicher, D. W.; Marchesi,
V. T.; Agre, P.; Hyun, B.; Gulati, G.: Mutant forms of spectrin alpha-subunits
in hereditary elliptocytosis. J. Clin. Invest. 80: 191-198, 1987.

16. Morton, N. E.: The detection and estimation of linkage between
the genes for elliptocytosis and the Rh blood type. Am. J. Hum. Genet. 8:
80-96, 1956.

17. Rao, D. C.; Keats, B. J.; Lalouel, J. M.; Morton, N. E.; Yee,
S.: A maximum likelihood map of chromosome 1. Am. J. Hum. Genet. 31:
680-696, 1979.

18. Ravindranath, Y.; Johnson, R. M.: Altered spectrin association
and membrane fragility without abnormal spectrin heat sensitivity
in a case of congenital hemolytic anemia. Am. J. Hemat. 20: 53-65,
1985.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Elliptocytosis

MISCELLANEOUS:
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the spectrin, alpha, erythrocytic-1 gene (SPTA1,
182860.0001)

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

*FIELD* ED
joanna: 05/18/2011

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

*FIELD* ED
carol: 04/30/2012
terry: 3/27/2012
terry: 3/18/2009
carol: 3/18/2009
mgross: 2/21/2008
terry: 4/30/1999
dkim: 7/21/1998
mimadm: 9/24/1994
carol: 5/13/1994
carol: 5/6/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/17/1992

MIM 182870
*RECORD*
*FIELD* NO
182870
*FIELD* TI
+182870 SPECTRIN, BETA, ERYTHROCYTIC; SPTB
;;SPECTRIN, BETA-I
SPHEROCYTOSIS, TYPE 2, INCLUDED; SPH2, INCLUDED;;
read moreSPHEROCYTOSIS, HEREDITARY, 2, INCLUDED; HS2, INCLUDED;;
ELLIPTOCYTOSIS 3, INCLUDED; EL3, INCLUDED
*FIELD* TX

CLONING

Winkelmann et al. (1988) cloned the SPTB gene; they estimated the size
of the mRNA to be 7.5 kb. Prchal et al. (1987) showed that the
reticulocyte beta-spectrin mRNA is 7.8 kb long.

Winkelmann et al. (1990) sequenced overlapping cDNA clones for the
entire coding sequence of beta-spectrin. The sequence encodes a
2,137-amino acid, 246-kD protein, consisting of 3 domains: domain I, at
the N-terminus, is a 272-amino acid region lacking resemblance to the
spectrin repetitive motif but showing striking homology at both
nucleotide and amino acid levels to the N-terminal 'actin-binding'
domains of alpha-actinin (102575) and dystrophin (300377); domain II
consists of 17 spectrin repeats; and domain III, 52 amino acid residues
at the C terminus, does not adhere to the spectrin repeat motif.

MAPPING

Kimberling et al. (1978) had found linkage of hereditary spherocytosis
with Gm type (determined by the IGHG locus, or loci, on chromosome
14q34; see 147100). In 15 families, the maximum lod score was 3.42 at a
recombination fraction of 22%. With the evidence that one form of
spherocytosis has a defect in beta-spectrin, this linkage information
could be added to the evidence of location of beta-spectrin on
chromosome 14. Watkins et al. (1987) mapped the beta-spectrin gene to
chromosome 14 by use of a cDNA probe in somatic cell hybrids.

Prchal et al. (1987) reported the isolation and characterization of a
human erythroid-specific beta-spectrin cDNA clone that encodes parts of
the beta-9 through beta-12 repeat segments. They used this cDNA as a
hybridization probe to assign the beta-spectrin gene to chromosome 14 by
hybridization to a panel of nitrocellulose filters containing DNA from
sorted human chromosomes. Closely linked RFLPs useful in the analysis of
congenital hemolytic anemias were described.

Winkelmann et al. (1988) assigned the SPTB gene to chromosome 14 by
hybridization to DNA from a well-characterized panel of mouse-human
somatic cell hybrids (Winkelmann et al., 1987).

By in situ hybridization with an erythroid beta-spectrin cDNA, Forget et
al. (1988) concluded that the beta-spectrin gene is located considerably
proximal to the IGH locus (147100), at 14q22-q23.2.

Forget et al. (1988) observed a kindred in which at least 3 members
showed recombination between hereditary spherocytosis and RFLPs defined
by the beta-spectrin clone. In the same kindred, alpha-spectrin and
protein 4.1 were also ruled out as sites of the mutation.

By in situ hybridization, Fukushima et al. (1990) concluded that the
SPTB gene is located in 14q23-q24.2.

Laurila et al. (1987) mapped the beta-spectrin gene to mouse chromosome
12. Birkenmeier et al. (1988) showed that the erythroid beta-spectrin
gene is tightly linked to the 'jaundiced' (ja) locus on mouse chromosome
12. This assignment was considered consistent with the hypothesis that
the defect in this disorder is the result of a mutation in the
beta-spectrin gene.

MOLECULAR GENETICS

- Spherocytosis Type 2

In a family with autosomal dominant spherocytosis, Goodman et al. (1982)
determined that the molecular defect is in the N-terminal portion of the
spectrin beta chain. In the family studied by Goodman et al. (1982),
Becker et al. (1993) identified a mutation in the SPTB gene
(182870.0007).

Gallagher and Forget (1998) tabulated 19 mutations of the SPTB gene that
cause hereditary spherocytosis.

Maciag et al. (2009) found that levels of SPTB mRNA were 20 to 80% lower
in unrelated patients with hereditary spherocytosis compared to
controls. Direct sequencing identified 5 different pathogenic mutations
in the SPTB gene (see, e.g., 182870.0015). Affected members of 1 family
showed 2 mutations, consistent with the greatest decrease (80%) in SPTB
mRNA. Maciag et al. (2009) noted that SPTB mutations tend to be unique
to each family studied.

- Elliptocytosis 3

Aksoy et al. (1974) described severe hemolytic anemia in a patient who
seemingly had 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 (McKusick, 1973). Now that
separate mutations in the beta-spectrin gene are known to cause either
spherocytosis or elliptocytosis, the genetic compound hypothesis is
particularly plausible.

Eber et al. (1988) found a truncated beta chain in affected members of a
large German family in which several members suffered in varying degrees
from a microcytic hemolytic anemia. The red cell morphology varied from
smooth elliptocytes to predominantly poikilocytes. The abnormal spectrin
made up about 30% of the total and was present almost entirely as the
dimer.

Ohanian et al. (1985) described a case of hemolytic anemia with
elliptocytosis in which a large part of the beta subunit of spectrin was
truncated. Coetzer and Zail (1981) and Dhermy et al. (1982) found
variants of the beta-subunit in patients with hereditary elliptocytosis.

Gallagher and Forget (1996) cataloged 15 reported beta-spectrin
mutations found in cases of hereditary elliptocytosis and hereditary
pyropoikilocytosis. Three were splicing mutations, 3 were deletions, 1
was an insertion, and the remainder were missense mutations.

*FIELD* AV
.0001
SPECTRIN SAINT CHAMOND
SPTB, BETA-IV DOMAIN

Pothier et al. (1989) found this variant in a French family.
Heterozygotes were clinically normal and showed no morphologic
abnormalities of red cells. The abnormality resided in the beta-IV
domain.

.0002
SPECTRIN TLEMCEN
SPTB, BETA-IV DOMAIN

Pothier et al. (1989) described this variant in an Algerian individual
who was heterozygous for the variant and was asymptomatic clinically
with morphologically normal red cells. The mutation was located in the
beta-IV domain. This 41-kD fragment is near the N terminus of the
beta-spectrin chain. The proband was also heterozygous for an alpha
mutant, spectrin Oran.

.0003
ELLIPTOCYTOSIS 3
SPTB, ALA2053PRO

Tse et al. (1989) studied the family of an infant with severe neonatal
hemolytic anemia with poikilocytosis. Biochemical studies were
consistent with the parents being heterozygous for alpha-I/74 hereditary
elliptocytosis and the proband being homozygous. Spectrin chain
reconstitution and RFLP linkage studies indicated, however, that the
primary defect resided in beta-spectrin. Nucleotide sequencing showed a
substitution that changed alanine residue 2053 to proline. Tse et al.
(1989) suggested a model of interaction of the alpha- and beta-spectrin
chains in such a way that a proline residue would disrupt the normal
helical structure of the complex, thereby impairing spectrin dimer
self-association and exposing the alpha chain to enhanced proteolysis.
Thus, this is an example of apparent abnormality in one polypeptide
resulting from a primary defect in another.

.0004
ELLIPTOCYTOSIS 3
SPECTRIN ROUEN
SPTB, EXON Y DEL

In a family with a chronic hemolytic form of hereditary elliptocytosis
and, by biochemical analysis, a truncated beta-spectrin chain with
deletion of a peptide fragment near the C-terminus, Gallagher et al.
(1990) showed that the next-to-last exon of beta-spectrin (exon Y) was
absent. Nucleotide sequencing showed a mutation in the 5-prime donor
consensus splice site of the intron following the Y exon, TGG/GTGAGT to
TGG/GTTAGT, in 1 allele. The truncated donor spectrin chain was thought
to be due to splicing out of exon Y because of the mutation, resulting
in exon skipping. Garbarz et al. (1991) stated that this was, to their
knowledge, the first documented example of exon skipping as the cause of
a shortened beta-spectrin chain in a case of hereditary elliptocytosis.
The exon skip resulted in a loss of 17 amino acids and created a
frameshift with the synthesis of 33 novel amino acids before premature
chain termination 14 residues upstream from the normal carboxy-terminus
of the beta-spectrin chain, giving a mutant beta-spectrin chain 31 amino
acids shorter than the normal chain.

.0005
ELLIPTOCYTOSIS 3
SPTB, 2-BP INS, FS2077TER

Pothier et al. (1987) described a new defect in the beta chain of
spectrin, designated spectrin Nice, causing elliptocytosis with
hemolytic anemia. The beta chain was truncated, resulting in an
additional band migrating between the spectrin beta chain and ankyrin.
It represented 30% of the total beta chain. Pothier et al. (1987)
considered this to be a new mutation. By nucleotide sequencing, Tse et
al. (1991) showed a normal beta-spectrin cDNA sequence from position
6153 to position 6231, at which point the sequencing pattern became a
superimposition of 2 different sequencing ladders, presumably
corresponding to the 2 beta-spectrin alleles of the propositus. An
insertion of 2 extra bases, GA, was demonstrated between nucleotides
6232 and 6233 in exon 10. The 2 extra bases were inserted after the
first base of codon 2046. The insertion created a frameshift in the
C-terminal region of the beta-spectrin chain. A new stop codon had been
created 31 residues downstream in the new reading frame. The amino acid
sequence of the abnormal chain showed a net loss of 61 residues which
corresponded to a size difference of roughly 6 kD from the normal.

.0006
ELLIPTOCYTOSIS 3
SPTB, 1-BP DEL, FS2075TER

In a Japanese patient with elliptocytosis and uncompensated hemolysis of
moderate severity, Kanzaki et al. (1992) demonstrated a 1-bp deletion in
codon 2059 in exon 10 of the SPTB gene. The change in code from GCCAGC
to GCAGCT changed ala-ser to ala-ala. A missense sequence extended down
to a new codon 2075. Serine-2060, a potential phosphorylation site, was
replaced by alanine. The shortened beta chain failed to undergo
phosphorylation in vitro. This mutation, designated spectrin Tokyo,
shared the same TGA stop codon, overlapping normal codons 2076 and 2077
(CTGAAA), as spectrin Nice (182870.0005), which is caused by a 2-bp
insertion in codon 2046 and contains 2,076 amino acids.

.0007
SPHEROCYTOSIS, TYPE 2, AUTOSOMAL DOMINANT
SPECTRIN KISSIMMEE
SPTB, TRP202ARG

There is asymmetry in the relative synthetic rates of alpha- and
beta-spectrin; the synthesis of alpha- and beta-spectrin is threefold in
excess of beta-spectrin synthesis. Spectrin assembly in the membrane
appears to be rate limited by the beta chain. Therefore, one could
predict that defects in beta-spectrin would be manifest in the
heterozygous state and result in dominantly inherited conditions. In
contrast, defects in alpha-spectrin may not be manifest until the
homozygous state is reached, since the alpha chains are synthesized in
excess of the beta chains. Becker et al. (1993) were the first to
identify a point mutation in the SPTB gene and to demonstrate a
beta-spectrin mutation as the cause of autosomal dominant hereditary
spherocytosis. The family had previously been studied by Goodman et al.
(1982) and Wolfe et al. (1982), who had shown that approximately 40% of
the spectrin was unable to bind protein 4.1 (EPB41; Montreal 500).
Becker et al. (1993) found a TGG (trp)-to-CGG (arg) change at codon 202.
The mutation was not found in 20 other kindreds. The mutation was
located within a conserved sequence among spectrin-like proteins and may
define an amino acid critical for protein 4.1 binding.

.0008
PYROPOIKILOCYTOSIS, HEREDITARY
ELLIPTOCYTOSIS 3, INCLUDED
SPTB, ALA2018GLY

Sahr et al. (1993) defined the molecular defect, designated spectrin
Cagliari, responsible for clinically asymptomatic hereditary
elliptocytosis and hereditary pyropoikilocytosis (266140) in 2 unrelated
families from Cagliari, Sardinia. One family, earlier reported by
Coetzer et al. (1990), was ascertained through 2 daughters with severe
hemolytic anemia and findings on blood smears consistent with the
diagnosis of pyropoikilocytosis. Both parents, who were related, were
clinically asymptomatic but showed mild hemolysis and, like one other
daughter, had approximately 20% elliptocytes. In the second family, the
parents were also consanguineous but clinically normal. A son had severe
neonatal hemolysis and findings of pyropoikilocytosis. The anemia was
transfusion-dependent in all 3 with HPP; transfusion dependence was
relieved by splenectomy in 1. Following linkage studies which were most
consistent with a beta-spectrin mutation, a nucleotide change was
identified in codon 2018 of the SPTB gene resulting in an ala-to-gly
substitution in the first helical domain of beta-spectrin repeat 17.
Because glycine is a strong helix breaker, the change was predicted to
disrupt the conformation of this helical domain, which must play a
direct role in alpha-beta interdimer interactions. The 3 persons with
HPP were homozygous for the defect.

.0009
SPECTRIN PROVIDENCE
SPTB, SER2019PRO

Gallagher et al. (1995) studied a Laotian kindred in which 4
third-trimester fetal losses occurred, associated with severe
Coombs-negative hemolytic anemia and extensive extramedullary
erythropoiesis. Postmortem examination of 2 infants revealed overt
hydrops fetalis. Studies of erythrocytes and erythrocyte membranes from
the parents revealed abnormal membrane mechanical stability as well as
structural and functional abnormalities in spectrin. Genetic studies
identified a point mutation of the SPTB gene, resulting in an amino acid
replacement, S2019P, in the C-terminal region of erythrocyte
beta-spectrin that is critical for normal spectrin self-association.
Both parents and 2 living children were heterozygous for this mutation.
As determined by analysis of DNA obtained from autopsy material, the 3
deceased infants were homozygous for the mutation. The variant was named
spectrin Providence.

.0010
SPHEROCYTOSIS, TYPE 2, AUTOSOMAL DOMINANT
SPECTRIN DURHAM
SPTB, EX22-23 DEL

In an apparent new-mutation case of hereditary spherocytosis, Hassoun et
al. (1995) demonstrated heterozygosity for a deletion of exons 22 and 23
of the SPTB gene. Although the mutated gene was efficiently transcribed
and its mRNA abundant in reticulocytes, the mutant protein was normally
synthesized in erythroid progenitor cells, and the stability of the
mutant protein in the cytoplasm of erythroblasts paralleled that of the
normal beta-spectrin, the abnormal protein was inefficiently
incorporated into the membrane of the erythroblasts. Hassoun et al.
(1995) presented evidence that misincorporation into the cell membrane
resulted from conformational changes of the beta-spectrin subunit
affecting the binding of the abnormal heterodimer to ankyrin. The rate
of synthesis of alpha-spectrin is 3 times that of beta-spectrin, and
therefore the availability of beta-spectrin determines the rate of
assembly of the spectrin heterodimers on the membrane (Hanspal and
Palek, 1987, Hanspal et al., 1992). No mutations of alpha-spectrin had
been reported as the cause of hereditary spherocytosis. Mutations in
band 3 (109270) and particularly in ankyrin (612641) had previously been
described in dominantly inherited spherocytosis. One previous example of
a heterozygous beta-spectrin mutation, spectrin Kissimmee, had been
described (182870.0007).

.0011
ANEMIA, NEONATAL HEMOLYTIC, FATAL AND NEAR-FATAL
SPTB, LEU2025ARG

Gallagher et al. (1997) found homozygosity for a mutation in the SPTB
gene in an infant with severe nonimmune hemolytic anemia and hydrops
fetalis at birth. His neonatal course was marked by ongoing hemolysis
requiring repeated erythrocyte transfusions. He had remained
transfusion-dependent for more than 2 years. A previous sib born with
hemolytic anemia and hydrops fetalis died on the second day of life.
Peripheral blood smears from both parents revealed rare elliptocytes.
Examination of the patient erythrocyte membranes revealed abnormal
mechanical stability, as well as structural and functional abnormalities
in spectrin. The proband and his deceased sister were found to be
homozygous for an L2025R mutation in the region of spectrin that is
critical for normal function. The importance of leucine in this position
of the proposed triple helical model of spectrin repeats was highlighted
by its evolutionary conservation in all beta-spectrins from Drosophila
to humans. Molecular modeling demonstrated the disruption of hydrophobic
interactions in the interior of the triple helix critical for spectrin
function caused by the replacement of the hydrophobic, uncharged leucine
by a hydrophilic, positively charged arginine. Gallagher et al. (1997)
noted that this mutation must also be expressed in beta-spectrin found
in muscle, yet pathologic and immunohistochemical examination of
skeletal muscle from the deceased sib was unremarkable. The parents were
Laotian and apparently nonconsanguineous.

.0012
ELLIPTOCYTOSIS 3 DUE TO SPECTRIN COSENZA
SPTB, ARG2064PRO

In a Calabrian family in Southern Italy, Qualtieri et al. (1997) found
that hereditary elliptocytosis in the heterozygous state was
asymptomatic and associated with a defect in spectrin dimer self
association and an increase of the alpha(I/74) kD fragment from the
alpha-chain after partial tryptic digestion of spectrin. By SSCP
followed by DNA sequencing, they identified a C-to-G substitution at
position 6284 of the SPTB gene. The corresponding substitution at the
protein level was arg2064pro of the beta-spectrin chain.

.0013
ELLIPTOCYTOSIS 3 DUE TO SPECTRIN PROMISSAO
SPTB, MET1VAL

Basseres et al. (1998) described the first example of a translation
initiation mutation in the SPTB gene. A Brazilian family with hereditary
spherocytosis in 8 individuals in 2 generations carried the mutation.
The propositus was a 28-year-old black man with compensated hemolytic
disease with splenomegaly, hyperbilirubinemia, increased osmotic
fragility, and a regular number of spherocytes and acanthocytes in the
blood smear. Affected members of the family were heterozygous for an
A-to-G substitution converting the translation initiation codon from ATG
to GTG. The mutation would be expected to convert the initiation
methionine to a valine. Affected members would have only 1 functional
allele and, as beta-spectrin quantities are probably limiting for
membrane assembly, this would account for the picture of spherocytosis.

.0014
SPHEROCYTOSIS, TYPE 2, AUTOSOMAL DOMINANT
SPECTRIN S-TA BARBARA
SPTB, 1-BP DEL

Basseres et al. (2001) identified beta-spectrin S-ta Barbara in a
25-year-old woman of Italian origin who presented with hemolytic anemia
with splenomegaly, hyperbilirubinemia, increased osmotic fragility of
the red cells, and many spherocytes and acanthocytes in the blood smear.
The mutation was a deletion of 1 cytosine at codon 638 in exon 14,
causing a frameshift and premature termination after an additional 31
amino acids. The mutant protein was not detected in red cell membranes
or in other cellular compartments, but detectable levels of mutant mRNA
were found in the patient. The mutation was not present in the patient's
parents but was present in her affected brother, suggesting mosaicism.
DNA analyses of different tissues of the parents failed to reveal the
mutation. A fingerprinting test using highly polymorphic markers failed
to exclude paternity with a high confidence index in relation to both
the patient and her affected brother.

.0015
SPHEROCYTOSIS, TYPE 2, AUTOSOMAL DOMINANT
SPTB, ARG1756TER

In sibs with hereditary spherocytosis, Maciag et al. (2009) found an
approximately 25% decrease in SPTB mRNA compared to controls. Direct
sequencing of the SPTB gene identified a heterozygous 5268C-T transition
in exon 26, resulting in an arg1756-to-ter (R1756X) substitution. The
findings suggested that the mutation did not lead to complete
nonsense-mediated mRNA decay, perhaps because of its location. Maciag et
al. (2009) postulated that the shortened protein was incorporated into
the erythrocyte membrane, leading to mechanical instability.

*FIELD* RF
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16. Gallagher, P. G.; Weed, S. A.; Tse, W. T.; Benoit, L.; Morrow,
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24. Laurila, P.; Cioe, L.; Kozak, C. A.; Curtis, P. J.: Assignment
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*FIELD* CS

Heme:
Hemolytic anemia with elliptocytosis (e.g. Elliptocytosis .0003);
Spherocytosis (e.g. Spherocytosis, autosomal dominant .0007);
Pyropoikilocytosis (e.g. Spectrin Cagliari .0008)

Skin:
Jaundice

Misc:
Spectrin, beta subunit defect

Lab:
Hyperbilirubinemia;
Poikilocytosis

Inheritance:
Autosomal dominant (14q23-q24.2)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/28/2010
Victor A. McKusick - updated: 1/24/2002
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick -updated: 3/30/1998
Victor A. McKusick - updated: 9/12/1997
Victor A. McKusick - updated: 5/14/1997
Victor A. McKusick - updated: 2/20/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 04/04/2013
carol: 3/16/2012
wwang: 2/17/2010
ckniffin: 1/28/2010
carol: 3/18/2009
carol: 2/26/2009
carol: 2/19/2009
carol: 3/17/2004
cwells: 3/13/2002
carol: 2/7/2002
carol: 2/6/2002
mcapotos: 2/4/2002
terry: 1/24/2002
carol: 10/20/2000
carol: 6/8/2000
mcapotos: 6/7/2000
terry: 3/1/1999
carol: 2/27/1999
terry: 7/24/1998
dkim: 7/21/1998
alopez: 3/30/1998
terry: 3/25/1998
mark: 9/19/1997
terry: 9/12/1997
alopez: 5/20/1997
terry: 5/19/1997
terry: 5/14/1997
mark: 2/20/1997
terry: 2/13/1997
mark: 5/28/1996
terry: 5/24/1996
terry: 3/26/1996
mark: 1/29/1996
mark: 1/27/1996
terry: 1/18/1996
mark: 4/10/1995
mimadm: 3/25/1995
carol: 12/22/1993
carol: 12/20/1993
carol: 12/16/1993
carol: 9/16/1993