RBCC Red Blood Cell Collection

EPB41 (E41P) [Confidence: high (present in two of the MS resources)]
Protein 4.1; P4.1 (4.1R; Band 4.1; EPB4.1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00003921
IPI00003921 Splice isoform 1 of P11171 Protein 4.1 Splice isoform 1 of P11171 Protein 4.1 membrane 11 27 3 18 26 11 26 12 146 2 n/a n/a n/a 24 n/a 5 n/a 36 n/a 26 cytoskeleton HIEVTVPTSNGDQTQK (only unique peptide existing, found at least 3 times) found at its expected molecular weight found at molecular weight

Comments
Isoform P11171-4 was detected.

UniProt P11171
ID 41_HUMAN Reviewed; 864 AA.
AC P11171; B1ALH8; B1ALH9; D3DPM9; D3DPN0; P11176; Q14245; Q5TB35;
read moreAC Q5VXN8; Q8IXV9; Q9Y578; Q9Y579;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 07-MAR-2006, sequence version 4.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Protein 4.1;
DE Short=P4.1;
DE AltName: Full=4.1R;
DE AltName: Full=Band 4.1;
DE AltName: Full=EPB4.1;
GN Name=EPB41; Synonyms=E41P;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND PROTEIN SEQUENCE OF
RP 378-393.
RC TISSUE=Reticulocyte;
RX PubMed=3467321; DOI=10.1073/pnas.83.24.9512;
RA Conboy J.G., Kan Y.W., Shohet S.B., Mohandas N.;
RT "Molecular cloning of protein 4.1, a major structural element of the
RT human erythrocyte membrane skeleton.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:9512-9516(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 5 AND 6).
RX PubMed=3223413;
RA Tang T.K., Leto T.L., Marchesi V.T., Benz E.J. Jr.;
RT "Expression of specific isoforms of protein 4.1 in erythroid and non-
RT erythroid tissues.";
RL Adv. Exp. Med. Biol. 241:81-95(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 5 AND 6).
RX PubMed=3375238; DOI=10.1073/pnas.85.11.3713;
RA Tang T.K., Leto T.L., Correas I., Alonso M.A., Marchesi V.T.,
RA Benz E.J. Jr.;
RT "Selective expression of an erythroid-specific isoform of protein
RT 4.1.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:3713-3717(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=2022644;
RA Conboy J.G., Chan J.Y.C., Chasis J.A., Kan Y.W., Mohandas N.;
RT "Tissue- and development-specific alternative RNA splicing regulates
RT expression of multiple isoforms of erythroid membrane protein 4.1.";
RL J. Biol. Chem. 266:8273-8280(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Huang S.C., Wang C., Lichtenauer U., Vortmeyer A., Zhuang Z.;
RT "Sequence of protein 4.1 from a human neuroblastoma cell line: LAN5.";
RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC TISSUE=Brain;
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 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 157-227, AND VARIANT ILE-214.
RA Lichtenauer U., Huang S.C., Vortmeyer A., Zhuang Z.;
RT "Valine to isoleucine polymorphism in exon 4 of human protein 4.1.";
RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE OF 669-864 (ISOFORM 4), AND ALTERNATIVE SPLICING.
RX PubMed=3194408; DOI=10.1073/pnas.85.23.9062;
RA Conboy J.G., Chan J., Mohandas N., Kan Y.W.;
RT "Multiple protein 4.1 isoforms produced by alternative splicing in
RT human erythroid cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:9062-9065(1988).
RN [11]
RP PROTEIN SEQUENCE OF 534-541; 693-701 AND 793-794, AND PHOSPHORYLATION
RP AT SERINE RESIDUES.
RX PubMed=2171679; DOI=10.1016/0167-4889(90)90095-U;
RA Horne W.C., Prinz W.C., Tang E.K.;
RT "Identification of two cAMP-dependent phosphorylation sites on
RT erythrocyte protein 4.1.";
RL Biochim. Biophys. Acta 1055:87-92(1990).
RN [12]
RP PROTEIN SEQUENCE OF 648-714.
RX PubMed=3531202;
RA Correas I., Speicher D.W., Marchesi V.T.;
RT "Structure of the spectrin-actin binding site of erythrocyte protein
RT 4.1.";
RL J. Biol. Chem. 261:13362-13366(1986).
RN [13]
RP STRUCTURE OF CARBOHYDRATES.
RX PubMed=2808371;
RA Inaba M., Maede Y.;
RT "O-N-acetyl-D-glucosamine moiety on discrete peptide of multiple
RT protein 4.1 isoforms regulated by alternative pathways.";
RL J. Biol. Chem. 264:18149-18155(1989).
RN [14]
RP PHOSPHORYLATION AT TYR-660 BY EGFR.
RX PubMed=1647028; DOI=10.1073/pnas.88.12.5222;
RA Subrahmanyan G., Bertics P.J., Anderson R.A.;
RT "Phosphorylation of protein 4.1 on tyrosine-418 modulates its function
RT in vitro.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:5222-5226(1991).
RN [15]
RP INTERACTION WITH DLG1.
RX PubMed=7937897; DOI=10.1073/pnas.91.21.9818;
RA Lue R.A., Marfatia S.M., Branton D., Chishti A.H.;
RT "Cloning and characterization of hdlg: the human homologue of the
RT Drosophila discs large tumor suppressor binds to protein 4.1.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:9818-9822(1994).
RN [16]
RP INTERACTION WITH CALMODULIN.
RX PubMed=10692436; DOI=10.1074/jbc.275.9.6360;
RA Nunomura W., Takakuwa Y., Parra M., Conboy J.G., Mohandas N.;
RT "Ca(2+)-dependent and Ca(2+)-independent calmodulin binding sites in
RT erythrocyte protein 4.1. Implications for regulation of protein 4.1
RT interactions with transmembrane proteins.";
RL J. Biol. Chem. 275:6360-6367(2000).
RN [17]
RP INTERACTION WITH CENPJ.
RX PubMed=11003675; DOI=10.1128/MCB.20.20.7813-7825.2000;
RA Hung L.-Y., Tang C.J., Tang T.K.;
RT "Protein 4.1 R-135 interacts with a novel centrosomal protein (CPAP)
RT which is associated with the gamma-tubulin complex.";
RL Mol. Cell. Biol. 20:7813-7825(2000).
RN [18]
RP CHARACTERIZATION OF C-TERMINAL DOMAIN.
RX PubMed=11432737; DOI=10.1046/j.1432-1327.2001.02276.x;
RA Scott C., Phillips G.W., Baines A.J.;
RT "Properties of the C-terminal domain of 4.1 proteins.";
RL Eur. J. Biochem. 268:3709-3717(2001).
RN [19]
RP SUBCELLULAR LOCATION, AND ALTERNATIVE SPLICING.
RX PubMed=12427749; DOI=10.1074/jbc.M201521200;
RA Luque C.M., Perez-Ferreiro C.M., Perez-Gonzalez A., Englmeier L.,
RA Koffa M.D., Correas I.;
RT "An alternative domain containing a leucine-rich sequence regulates
RT nuclear cytoplasmic localization of protein 4.1R.";
RL J. Biol. Chem. 278:2686-2691(2003).
RN [20]
RP MUTAGENESIS OF THR-60 AND SER-712, AND PHOSPHORYLATION AT THR-60 AND
RP SER-712.
RX PubMed=15525677; DOI=10.1091/mbc.E04-05-0426;
RA Huang S.-C., Liu E.S., Chan S.-H., Munagala I.D., Cho H.T.,
RA Jagadeeswaran R., Benz E.J. Jr.;
RT "Mitotic regulation of protein 4.1R involves phosphorylation by cdc2
RT kinase.";
RL Mol. Biol. Cell 16:117-127(2005).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188; SER-191; SER-555
RP AND SER-712, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-84; SER-85; SER-188 AND
RP SER-712, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
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 [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14; SER-149; SER-151 AND
RP SER-152, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 210-488.
RX PubMed=11017195; DOI=10.1038/82819;
RA Han B.-G., Nunomura W., Takakuwa Y., Mohandas N., Jap B.K.;
RT "Protein 4.1R core domain structure and insights into regulation of
RT cytoskeletal organization.";
RL Nat. Struct. Biol. 7:871-875(2000).
CC -!- FUNCTION: Protein 4.1 is a major structural element of the
CC erythrocyte membrane skeleton. It plays a key role in regulating
CC membrane physical properties of mechanical stability and
CC deformability by stabilizing spectrin-actin interaction. Recruits
CC DLG1 to membranes.
CC -!- SUBUNIT: Binds with a high affinity to glycophorin and with lower
CC affinity to band III protein. Associates with the nuclear mitotic
CC apparatus. Binds calmodulin, CENPJ and DLG1. Also found to
CC associate with contractile apparatus and tight junctions.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm, cell
CC cortex. Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1;
CC IsoId=P11171-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P11171-2; Sequence=VSP_000470;
CC Name=3;
CC IsoId=P11171-3; Sequence=VSP_000468, VSP_000471;
CC Name=4; Synonyms=Erythroid;
CC IsoId=P11171-4; Sequence=VSP_000468, VSP_000470, VSP_000473;
CC Name=5; Synonyms=Non-erythroid A;
CC IsoId=P11171-5; Sequence=VSP_000469, VSP_000470, VSP_000472;
CC Name=6; Synonyms=Non-erythroid B;
CC IsoId=P11171-6; Sequence=VSP_000468, VSP_000469, VSP_000470,
CC VSP_000472;
CC Name=7;
CC IsoId=P11171-7; Sequence=VSP_000471, VSP_012872, VSP_012873;
CC -!- PTM: Phosphorylated at multiple sites by different protein kinases
CC and each phosphorylation event selectively modulates the protein's
CC functions.
CC -!- PTM: Phosphorylation on Tyr-660 reduces the ability of 4.1 to
CC promote the assembly of the spectrin/actin/4.1 ternary complex.
CC -!- PTM: O-glycosylated; contains N-acetylglucosamine side chains in
CC the C-terminal domain.
CC -!- DISEASE: Elliptocytosis 1 (EL1) [MIM:611804]: A Rhesus-linked form
CC 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: Hereditary pyropoikilocytosis (HPP) [MIM:266140]:
CC Autosomal recessive hematologic disorder characterized by
CC hemolytic anemia, microspherocytosis, poikilocytosis, and an
CC unusual thermal sensitivity of red cells. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 FERM domain.
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DR EMBL; M14993; AAA35795.1; -; mRNA.
DR EMBL; J03796; AAA35793.1; -; mRNA.
DR EMBL; J03796; AAA35794.1; -; mRNA.
DR EMBL; M61733; AAA35797.1; -; mRNA.
DR EMBL; AF156225; AAD42222.1; -; mRNA.
DR EMBL; AL138785; CAI21967.1; -; Genomic_DNA.
DR EMBL; AL357500; CAI21967.1; JOINED; Genomic_DNA.
DR EMBL; AL138785; CAI21966.1; -; Genomic_DNA.
DR EMBL; AL357500; CAI21966.1; JOINED; Genomic_DNA.
DR EMBL; AL138785; CAI21968.1; -; Genomic_DNA.
DR EMBL; AL138785; CAI21969.1; -; Genomic_DNA.
DR EMBL; AL357500; CAI21969.1; JOINED; Genomic_DNA.
DR EMBL; AL138785; CAI21970.1; -; Genomic_DNA.
DR EMBL; AL357500; CAI21970.1; JOINED; Genomic_DNA.
DR EMBL; AL357500; CAH71636.1; -; Genomic_DNA.
DR EMBL; AL138785; CAH71636.1; JOINED; Genomic_DNA.
DR EMBL; AL357500; CAH71637.1; -; Genomic_DNA.
DR EMBL; AL138785; CAH71637.1; JOINED; Genomic_DNA.
DR EMBL; AL357500; CAH71638.1; -; Genomic_DNA.
DR EMBL; AL138785; CAH71638.1; JOINED; Genomic_DNA.
DR EMBL; AL357500; CAH71639.1; -; Genomic_DNA.
DR EMBL; AL138785; CAH71639.1; JOINED; Genomic_DNA.
DR EMBL; CH471059; EAX07663.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07665.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07667.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07668.1; -; Genomic_DNA.
DR EMBL; BC039079; AAH39079.1; -; mRNA.
DR EMBL; AF156226; AAD42223.1; -; Genomic_DNA.
DR PIR; A39810; MMHUE4.
DR RefSeq; NP_001159477.1; NM_001166005.1.
DR RefSeq; NP_001159478.1; NM_001166006.1.
DR RefSeq; NP_004428.1; NM_004437.3.
DR RefSeq; NP_976217.1; NM_203342.2.
DR RefSeq; XP_005245818.1; XM_005245761.1.
DR RefSeq; XP_005245821.1; XM_005245764.1.
DR UniGene; Hs.175437; -.
DR UniGene; Hs.708933; -.
DR UniGene; Hs.712722; -.
DR PDB; 1GG3; X-ray; 2.80 A; A/B/C=210-488.
DR PDB; 2RQ1; NMR; -; A=292-396.
DR PDB; 3QIJ; X-ray; 1.80 A; A/B=211-488.
DR PDBsum; 1GG3; -.
DR PDBsum; 2RQ1; -.
DR PDBsum; 3QIJ; -.
DR DisProt; DP00678; -.
DR ProteinModelPortal; P11171; -.
DR SMR; P11171; 208-519.
DR DIP; DIP-17032N; -.
DR IntAct; P11171; 4.
DR MINT; MINT-1208648; -.
DR PhosphoSite; P11171; -.
DR UniCarbKB; P11171; -.
DR DMDM; 90101808; -.
DR PaxDb; P11171; -.
DR PRIDE; P11171; -.
DR DNASU; 2035; -.
DR Ensembl; ENST00000343067; ENSP00000345259; ENSG00000159023.
DR Ensembl; ENST00000347529; ENSP00000290100; ENSG00000159023.
DR Ensembl; ENST00000349460; ENSP00000317597; ENSG00000159023.
DR Ensembl; ENST00000356093; ENSP00000348397; ENSG00000159023.
DR Ensembl; ENST00000373797; ENSP00000362903; ENSG00000159023.
DR Ensembl; ENST00000373798; ENSP00000362904; ENSG00000159023.
DR Ensembl; ENST00000373800; ENSP00000362906; ENSG00000159023.
DR GeneID; 2035; -.
DR KEGG; hsa:2035; -.
DR UCSC; uc001brm.2; human.
DR CTD; 2035; -.
DR GeneCards; GC01P029213; -.
DR HGNC; HGNC:3377; EPB41.
DR HPA; HPA028414; -.
DR MIM; 130500; gene.
DR MIM; 266140; phenotype.
DR MIM; 611804; phenotype.
DR neXtProt; NX_P11171; -.
DR Orphanet; 98864; Common hereditary elliptocytosis.
DR Orphanet; 98865; Homozygous hereditary elliptocytosis.
DR PharmGKB; PA27810; -.
DR eggNOG; NOG242913; -.
DR HOVERGEN; HBG007777; -.
DR InParanoid; P11171; -.
DR KO; K06107; -.
DR OMA; HEDLTKN; -.
DR OrthoDB; EOG7Z69BP; -.
DR PhylomeDB; P11171; -.
DR ChiTaRS; EPB41; human.
DR EvolutionaryTrace; P11171; -.
DR GeneWiki; EPB41; -.
DR GenomeRNAi; 2035; -.
DR NextBio; 8259; -.
DR PMAP-CutDB; B1ALH9; -.
DR PRO; PR:P11171; -.
DR ArrayExpress; P11171; -.
DR Bgee; P11171; -.
DR CleanEx; HS_EPB41; -.
DR Genevestigator; P11171; -.
DR GO; GO:0019898; C:extrinsic to membrane; IEA:InterPro.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
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; TAS:BHF-UCL.
DR GO; GO:0005545; F:1-phosphatidylinositol binding; IDA:UniProtKB.
DR GO; GO:0030507; F:spectrin binding; TAS:BHF-UCL.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR GO; GO:0030036; P:actin cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0008015; P:blood circulation; TAS:ProtInc.
DR GO; GO:0030866; P:cortical actin cytoskeleton organization; IEA:InterPro.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:BHF-UCL.
DR Gene3D; 1.20.80.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR008379; Band_4.1_C.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR019750; Band_41_fam.
DR InterPro; IPR021187; Band_41_protein.
DR InterPro; IPR000798; Ez/rad/moesin_like.
DR InterPro; IPR014847; FERM-adjacent.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR019747; FERM_CS.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR018979; FERM_N.
DR InterPro; IPR018980; FERM_PH-like_C.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR007477; SAB_dom.
DR Pfam; PF05902; 4_1_CTD; 1.
DR Pfam; PF08736; FA; 1.
DR Pfam; PF09380; FERM_C; 1.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF09379; FERM_N; 1.
DR Pfam; PF04382; SAB; 1.
DR PIRSF; PIRSF002304; Membrane_skeletal_4_1; 1.
DR PRINTS; PR00935; BAND41.
DR PRINTS; PR00661; ERMFAMILY.
DR SMART; SM00295; B41; 1.
DR SUPFAM; SSF47031; SSF47031; 1.
DR PROSITE; PS00660; FERM_1; 1.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Actin-binding; Alternative splicing; Calmodulin-binding;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Elliptocytosis; Glycoprotein; Hereditary hemolytic anemia; Nucleus;
KW Phosphoprotein; Polymorphism; Pyropoikilocytosis; Reference proteome.
FT CHAIN 1 864 Protein 4.1.
FT /FTId=PRO_0000219390.
FT DOMAIN 210 491 FERM.
FT REGION 494 614 Hydrophilic.
FT REGION 615 713 Spectrin--actin-binding.
FT REGION 714 864 C-terminal (CTD).
FT MOD_RES 14 14 Phosphoserine.
FT MOD_RES 60 60 Phosphothreonine; by CDK1.
FT MOD_RES 84 84 Phosphoserine.
FT MOD_RES 85 85 Phosphoserine.
FT MOD_RES 149 149 Phosphoserine.
FT MOD_RES 151 151 Phosphoserine.
FT MOD_RES 152 152 Phosphoserine.
FT MOD_RES 188 188 Phosphoserine.
FT MOD_RES 191 191 Phosphoserine.
FT MOD_RES 222 222 Phosphotyrosine (By similarity).
FT MOD_RES 540 540 Phosphoserine (By similarity).
FT MOD_RES 542 542 Phosphoserine (By similarity).
FT MOD_RES 555 555 Phosphoserine.
FT MOD_RES 660 660 Phosphotyrosine; by EGFR.
FT MOD_RES 712 712 Phosphoserine; by CDK1.
FT VAR_SEQ 1 209 Missing (in isoform 3, isoform 4 and
FT isoform 6).
FT /FTId=VSP_000468.
FT VAR_SEQ 228 262 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_000469.
FT VAR_SEQ 616 648 Missing (in isoform 2, isoform 4, isoform
FT 5 and isoform 6).
FT /FTId=VSP_000470.
FT VAR_SEQ 635 648 Missing (in isoform 3 and isoform 7).
FT /FTId=VSP_000471.
FT VAR_SEQ 649 669 Missing (in isoform 5 and isoform 6).
FT /FTId=VSP_000472.
FT VAR_SEQ 729 734 PPLVKT -> VSTLST (in isoform 7).
FT /FTId=VSP_012872.
FT VAR_SEQ 735 864 Missing (in isoform 7).
FT /FTId=VSP_012873.
FT VAR_SEQ 772 805 Missing (in isoform 4).
FT /FTId=VSP_000473.
FT VARIANT 214 214 V -> I (in dbSNP:rs111642750).
FT /FTId=VAR_009122.
FT MUTAGEN 60 60 T->A: Loss of CDK1-mediated
FT phosphorylation. Abolishes targeting onto
FT the mitotic spindle; when associated with
FT A-712.
FT MUTAGEN 712 712 S->A: Loss of CDK1-mediated
FT phosphorylation. Abolishes targeting onto
FT the mitotic spindle; when associated with
FT A-60.
FT CONFLICT 51 51 Q -> H (in Ref. 5; AAD42222).
FT CONFLICT 76 76 S -> N (in Ref. 5; AAD42222).
FT CONFLICT 168 168 F -> S (in Ref. 9; AAD42223).
FT CONFLICT 259 259 A -> T (in Ref. 5; AAD42222).
FT CONFLICT 665 665 N -> S (in Ref. 5; AAD42222).
FT CONFLICT 669 669 E -> K (in Ref. 10; no nucleotide entry).
FT CONFLICT 679 679 K -> E (in Ref. 5; AAD42222).
FT CONFLICT 802 802 Q -> K (in Ref. 2; no nucleotide entry
FT and 3; AAA35793/AAA35794).
FT CONFLICT 852 852 K -> L (in Ref. 10; no nucleotide entry).
FT CONFLICT 863 863 D -> E (in Ref. 10; no nucleotide entry).
FT STRAND 211 215
FT STRAND 221 225
FT HELIX 232 243
FT HELIX 248 250
FT STRAND 251 258
FT STRAND 261 264
FT HELIX 271 274
FT TURN 275 277
FT STRAND 281 288
FT HELIX 293 295
FT HELIX 299 314
FT HELIX 322 337
FT HELIX 342 345
FT HELIX 350 352
FT STRAND 356 358
FT HELIX 361 372
FT HELIX 379 390
FT TURN 394 397
FT STRAND 399 404
FT STRAND 410 415
FT STRAND 417 424
FT STRAND 427 433
FT HELIX 434 436
FT STRAND 437 443
FT STRAND 446 451
FT STRAND 454 458
FT STRAND 461 466
FT HELIX 470 486
SQ SEQUENCE 864 AA; 97017 MW; B466E7A9D7FBF12B CRC64;
MTTEKSLVTE AENSQHQQKE EGEEAINSGQ QEPQQEESCQ TAAEGDNWCE QKLKASNGDT
PTHEDLTKNK ERTSESRGLS RLFSSFLKRP KSQVSEEEGK EVESDKEKGE GGQKEIEFGT
SLDEEIILKA PIAAPEPELK TDPSLDLHSL SSAETQPAQE ELREDPDFEI KEGEGLEECS
KIEVKEESPQ SKAETELKAS QKPIRKHRNM HCKVSLLDDT VYECVVEKHA KGQDLLKRVC
EHLNLLEEDY FGLAIWDNAT SKTWLDSAKE IKKQVRGVPW NFTFNVKFYP PDPAQLTEDI
TRYYLCLQLR QDIVAGRLPC SFATLALLGS YTIQSELGDY DPELHGVDYV SDFKLAPNQT
KELEEKVMEL HKSYRSMTPA QADLEFLENA KKLSMYGVDL HKAKDLEGVD IILGVCSSGL
LVYKDKLRIN RFPWPKVLKI SYKRSSFFIK IRPGEQEQYE STIGFKLPSY RAAKKLWKVC
VEHHTFFRLT STDTIPKSKF LALGSKFRYS GRTQAQTRQA SALIDRPAPH FERTASKRAS
RSLDGAAAVD SADRSPRPTS APAITQGQVA EGGVLDASAK KTVVPKAQKE TVKAEVKKED
EPPEQAEPEP TEAWKVEKTH IEVTVPTSNG DQTQKLAEKT EDLIRMRKKK RERLDGENIY
IRHSNLMLED LDKSQEEIKK HHASISELKK NFMESVPEPR PSEWDKRLST HSPFRTLNIN
GQIPTGEGPP LVKTQTVTIS DNANAVKSEI PTKDVPIVHT ETKTITYEAA QTDDNSGDLD
PGVLLTAQTI TSETPSSTTT TQITKTVKGG ISETRIEKRI VITGDADIDH DQVLVQAIKE
AKEQHPDMSV TKVVVHQETE IADE
//

MIM 130500
*RECORD*
*FIELD* NO
130500
*FIELD* TI
*130500 ERYTHROCYTE MEMBRANE PROTEIN BAND 4.1; EPB41
;;PROTEIN 4.1, RED BLOOD CELL TYPE; 4.1R;;
read moreEL1 GENE
*FIELD* TX

CLONING

Conboy et al. (1986) reported the molecular cloning and characterization
of human erythrocyte protein 4.1 cDNA and the complete amino acid
sequence of the protein. Probes prepared from the cloned erythrocyte
protein 4.1 cDNA hybridized with distinct mRNA species from a wide
variety of nonerythroid tissues, including brain, liver, placenta,
pancreas, and intestine, implying substantial homology between erythroid
and nonerythroid protein 4.1. Brain protein 4.1, also known as synapsin
I (313440), is the best characterized of the nonerythroid forms.

Tang et al. (1988) compared nucleotide sequences of mRNA encoding
erythroid and lymphoid protein 4.1 isoforms. The lymphoid protein 4.1
isoforms exhibited several nucleotide sequence motifs that appeared
either to be inserted into or deleted from the mRNA by alternative
splicing of a common mRNA precursor. One of the motifs, located within
the spectrin-actin binding domain, was found only in erythroid cells and
was specifically produced during erythroid cell maturation. Conboy et
al. (1988) demonstrated that alternative splicing accounts for multiple
isoforms of protein 4.1 in red cells. In his Figure 2, Conboy (1993)
provided a map of the alternative splicing of protein 4.1 mRNA,
emphasizing the total chromosome relative to many combinatorial splicing
possibilities among the exons of the EPB41 gene. There are, furthermore,
2 AUG initiation codons, 1 of which accounts for an N-terminal extension
on the 80-kD gene product.

By tissue screening, Baklouti et al. (1997) examined the complex pattern
of alternative splicing variants of the protein 4.1 gene. They noted
that many splicing variations occur in the spectrin/actin binding (SAB)
domain. In particular, they found a 51-bp exon that was expressed almost
exclusively in muscle.

GENE STRUCTURE

By genomic sequence analysis, Baklouti et al. (1997) determined that 22
exons spanning approximately 200 kb contain the entire erythroid and
nonerythroid coding sequences of the human protein 4.1 gene.

MAPPING

The protein 4.1 gene was mapped to chromosome 1pter-p32 (Conboy et al.,
1985, 1986) by hybridization to chromosomes sorted onto nitrocellulose
filters using a fluorescence-activated cell sorter. Studies of
translocations also localized the gene to chromosome 1pter-p32, the
region of the Rh gene (Kan, 1986). Thus, it seemed certain that the
protein 4.1 gene is mutant in Rh-linked elliptocytosis-1 (EL1; 611804).

Tang and Tang (1991) concluded that the EL1 gene is located in band
1p34.2-p33 on the basis of the FLpter value (the fractional length of
the total chromosome relative to the terminus of the short arm).

Parra et al. (1998) stated that the EPB41 gene is located on chromosome
1p33-p32.

Bahary et al. (1991) assigned the mouse Epb41 gene to chromosome 4.

GENE FUNCTION

The red cell membrane cytoskeletal network consists of spectrin (bands 1
and 2; see 182860 and 182870), actin (band 5; see 102630), and protein
4.1. Actin and protein 4.1 interact with spectrin at the junction of
spectrin heterotetramers. The resulting complex plays a critical role in
erythrocyte shape and deformability. (The protein band nomenclature
given here is that of Fairbanks et al., 1971.) Correas et al. (1986)
determined the complete primary structure of the functional site of
protein 4.1 involved in spectrin-actin associations. Antibodies against
2 different synthetic peptides of this portion of the protein inhibited
association between protein 4.1, spectrin, and actin.

Ponthier et al. (2006) stated that the 4.1R protein in early erythroid
progenitors, derived from transcripts in which exon 16 is skipped,
exhibits low affinity for spectrin and actin. In contrast, late-stage
erythroblasts include exon 16 and express a high-affinity isoform. This
stage-specific repression of exon 16 inclusion is mediated in part by
the binding of HNRNPA/B (602688) proteins to exonic splicing silencer
elements located within the exon. Ponthier et al. (2006) also found that
FOX1 (A2BP1; 605104) and FOX2 (RBM9; 612149) stimulate exon 16 splicing
into a 4.1R pre-mRNA minigene via specific binding to UGCAUG splicing
enhancer motifs downstream of exon 16.

MOLECULAR GENETICS

Conboy et al. (1986) showed by Southern blot analysis of genomic DNA
from an Algerian family that in affected members the mutant protein 4.1
gene had a DNA rearrangement upstream from the initiation codon for
translation. The mRNA from the mutant gene was aberrantly spliced.

Lambert et al. (1988) reported an elliptocytosis family in which an
apparent rearrangement of the coding region of the protein 4.1 gene led
to restriction fragment length polymorphism when DNA was tested using a
fragment of the cDNA that encompassed the coding region of the gene.

McGuire et al. (1988) described a distinct variant of protein 4.1 in
each of 3 families with elliptocytosis. Affected members of family C, of
Italian ancestry, had red cells with reduced content of protein 4.1 of
normal molecular mass (approximately 80 kD).

EVOLUTION

Tan et al. (2005) found that the EPB41 and EPB41L3 (605331) genes from
fish, bird, amphibian, and mammalian genomes exhibit shared features,
including alternative first exons and differential splicing acceptors in
exon 2. In all cases, the most 5-prime exon, exon 1A, splices
exclusively to a weaker internal acceptor site in exon 2, skipping a
fragment designated exon 2-prime. Conversely, alternative first exons 1B
and 1C always splice to the stronger first acceptor site, retaining exon
2-prime. These correlations were independent of cell type or species of
origin. Since exon 2-prime contains a translation initiation site,
splice variants generate protein isoforms with distinct N termini. Tan
et al. (2005) calculated that coupling between upstream promoters and
downstream splicing in EPB41 and EBP41L3 has been conserved for at least
500 million years.

ANIMAL MODEL

The complex EPB41 gene on human chromosome 1p encodes a diverse family
of protein 4.1R isoforms. The prototypic 80-kD 4.1R in mature
erythrocytes is a key component of the erythroid membrane skeleton that
regulates red cell morphology and mechanical stability. To study the
function of 4.1R in nucleated cells, Shi et al. (1999) generated mice
with complete deficiency of all 4.1R protein isoforms. These 4.1R-null
mice were viable, with moderate hemolytic anemia but no gross
abnormalities. Platelet morphology and function were essentially normal.
Nonerythroid 4.1R expression patterns revealed focal expression in
specific neurons in the brain and in select cells of other major organs,
challenging the view that 4.1R expression is widespread among
nonerythroid cells.

Epb41-knockout mice have fragmented red blood cells that lack
glycophorin C (GPC; see 110750). In Epb41-null murine erythroblasts,
Salomao et al. (2010) found that GPC distributed exclusively to the
nuclei, whereas in enucleating erythroblasts from wildtype bone marrow,
GPC partitioned almost exclusively to nascent reticulocytes, with little
or no GPC observed in plasma membranes of extruding nuclei. In contrast,
glycophorin A (GPA; see 111300) partitioning was not perturbed, and GPA
sorted to nascent reticulocytes in both Epb41-null and wildtype
enucleating erythroblasts. The findings indicated that GPC deficiency in
Epb41-null erythroblasts is attributable to markedly abnormal protein
partitioning during enucleation, and suggested that reticulocytes in
hereditary elliptocytosis 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
ELLIPTOCYTOSIS 1
EPB41, 318-BP DEL

This mutation was first reported by Feo et al. (1980) and Tchernia et
al. (1981) in homozygotes and heterozygotes and by Alloisio et al.
(1985) in heterozygotes. In this form of elliptocytosis (611804),
Takakuwa et al. (1986) demonstrated restitution of normal membrane
stability by incorporation of purified protein 4.1 into deficient red
cells by exchange hemolysis.

In an Algerian family with hereditary elliptocytosis caused by
deficiency of erythroid protein 4.1 (described by Tchernia et al., 1981;
defect partially characterized by Conboy et al., 1986), Conboy et al.
(1993) delineated the defect by study of erythroid and nonerythroid
cells in 1 of the homozygously affected sibs. The molecular lesion was
shown to involve deletion of the downstream AUG initiation codon in 4.1
mRNA, thus leading to the absence of protein 4.1 in red cells. In
contrast, isoforms that use the upstream AUG were detected in
nonerythroid cells, thus explaining the absence of manifestations in
other organ systems. The lesion consisted of a 318-nucleotide deletion
that encompassed the downstream AUG but left the upstream AUG intact.
Normally, multiple protein 4.1 isoforms are expressed in a variety of
tissues through complex alternative pre-mRNA splicing events, one
function of which is to regulate use of 2 alternative translation
initiation signals. Late erythroid cells express mainly the downstream
initiation site for synthesis of prototypic 80-kD isoforms; nonerythroid
cells in addition use an upstream site to encode higher molecular mass
isoform(s).

.0002
REMOVED FROM DATABASE
.0003
ELLIPTOCYTOSIS 1
PROTEIN 4.1(95)
EPB41, 369-BP DUP

In affected members of family N of Scottish-Irish descent, McGuire et
al. (1988) found heterozygosity for a high molecular weight form of
protein 4.1 at approximately 95 kD, referred to as protein 4.1(95).
Marchesi et al. (1990) described the site and nature of the insertion
resulting in protein 4.1(95) and the functional consequences of the
mutation. The elliptocytosis (611804) was mild without anemia. Protein
4.1(95) was found to contain an insertion of about 15 kD adjacent to the
spectrin/actin domain of the protein comprised, at least in part, of
repeated sequence. Conboy et al. (1990) used polymerase chain reaction
(PCR) techniques to clone and sequence mutant reticulocyte mRNAs and
correlate the duplication end points with exon boundaries of the gene.
Protein 4.1(95) mRNA was found to encode a protein with 2 spectrin/actin
binding domains by virtue of a 369-nucleotide duplication from the codon
for lys407 to that for gln529.

.0004
ELLIPTOCYTOSIS 1
PROTEIN 4.1(68/65)
EPB41, 240-BP DEL

In affected members of family G, of Italian descent, McGuire et al.
(1988) found heterozygosity for normal 4.1(80) and 2 low molecular
weight forms of protein 4.1 at about 68 and 65 kD, referred to as
protein 4.1(68/65). The mutation was associated with moderate
elliptocytosis (611804) and anemia. Protein 4.1(68/65) was found to lack
the entire spectrin/actin binding domain. Conboy et al. (1990)
demonstrated that protein 4.1(68/65) mRNA lacked sequences encoding the
functionally important spectrin-actin binding domain due to a
240-nucleotide deletion spanning the codons for lys407 to gly486.
Marchesi et al. (1990) described the site and nature of the deletions
resulting in protein 4.1(68/65) and the functional consequences of these
mutations.

.0005
ELLIPTOCYTOSIS 1
PROTEIN 4.1 MADRID
EPB41, MET1ARG

Dalla Venezia et al. (1992) studied homozygous hereditary elliptocytosis
(611804) in a Spanish patient whose parents were second cousins. He had
had intermittent jaundice and pallor since birth. During aplastic crisis
at the age of 31 years, the spleen was very large and was removed and
cholecystectomy for gallstones was also performed. Remarkable
hematologic improvement followed. The mother of the propositus was
healthy, although her blood smear showed elliptocytosis; the father was
deceased. Glycophorin C was sharply reduced. This finding, as in other
homozygous elliptocytosis cases, indicates that protein 4.1 stabilizes
glycophorin C (110750) in the membrane. Spectrin and actin were
slightly, yet significantly, diminished. Dalla Venezia et al. (1992)
demonstrated an abnormality in 4.1 cDNA, specifically an AUG-to-AGG
transversion in the downstream translation initiation codon, changing
methionine to arginine. No obvious disorders were noted in cell types
other than red cells or possibly sperm cells. The propositus, born in
1948, had infertility associated with azoospermia and a right
ureterocele. Whereas heterozygous 4.1(-) HE accounts for one-fourth to
one-third of all HE in Caucasians, the incidence of homozygous 4.1(-) HE
was, in the opinion of Dalla Venezia et al. (1992), lower than
anticipated. They suggested that some 4.1(-) HE alleles may not be
viable in the homozygous state by virtue of affecting all isoforms of
the protein and leaving all cells deficient in protein 4.1. This was the
first identification of a specific point mutation.

.0006
ELLIPTOCYTOSIS 1
PROTEIN 4.1 LILLE
EPB41, MET1THR

Like protein 4.1 Madrid (130500.0001), protein 4.1 Lille cause
elliptocytosis (611804) and results from a mutation in the downstream
translation start site (AUG-to-ACG). See Garbarz et al. (1995).

*FIELD* RF
1. Alloisio, N.; Morle, L.; Dorleac, E.; Gentilhomme, O.; Bachir,
D.; Guetarni, D.; Colonna, P.; Bost, M.; Zouaoui, Z.; Roda, L.; Roussel,
D.; Delaunay, J.: The heterozygous form of 4.1(-) hereditary elliptocytosis
[the 4.1(-) trait]. Blood 65: 46-51, 1985.

2. Bahary, N.; Zorich, G.; Pachter, J. E.; Leibel, R. L.; Friedman,
J. M.: Molecular genetic linkage maps of mouse chromosomes 4 and
6. Genomics 11: 33-47, 1991.

3. Baklouti, F.; Huang, S.-C.; Vulliamy, T. J.; Delaunay, J.; Benz,
E. J., Jr.: Organization of the human protein 4.1 genomic locus:
new insights into the tissue-specific alternative splicing of the
pre-mRNA. Genomics 39: 289-302, 1997.

4. Conboy, J.; Kan, Y. W.; Shohet, S. B.; Mohandas, N.: Molecular
cloning of protein 4.1, a major structural element of the human erythrocyte
membrane skeleton. Proc. Nat. Acad. Sci. 83: 9512-9516, 1986.

5. Conboy, J.; Marchesi, S.; Kim, R.; Agre, P.; Kan, Y. W.; Mohandas,
N.: Molecular analysis of insertion/deletion mutations in protein
4.1 in elliptocytosis. II. Determination of molecular genetic origins
of rearrangements. J. Clin. Invest. 86: 524-530, 1990.

6. Conboy, J.; Mohandas, N.; Tchernia, G.; Kan, Y. W.: Molecular
basis of hereditary elliptocytosis due to protein 4.1 deficiency. New
Eng. J. Med. 315: 680-685, 1986.

7. Conboy, J. G.: Structure, function, and molecular genetics of
erythroid membrane skeletal protein 4.1 in normal and abnormal red
blood cells. Seminars Hemat. 30: 58-73, 1993.

8. Conboy, J. G.; Chan, J.; Mohandas, N.; Kan, Y. W.: Multiple protein
4.1 isoforms produced by alternative splicing in human erythroid cells. Proc.
Nat. Acad. Sci. 85: 9062-9065, 1988.

9. Conboy, J. G.; Chasis, J. A.; Winardi, R.; Tchernia, G.; Kan, Y.
W.; Mohandas, N.: An isoform-specific mutation in the protein 4.1
gene results in hereditary elliptocytosis and complete deficiency
of protein 4.1 in erythrocytes but not in nonerythroid cells. J.
Clin. Invest. 91: 77-82, 1993.

10. Conboy, J. G.; Mohandas, N.; Wang, C.; Tchernia, G.; Shohet, S.
B.; Kan, Y. W.: Molecular cloning and characterization of the gene
coding for red cell membrane skeletal protein 4.1. (Abstract) Blood 66
(suppl. 1): 31A, 1985.

11. Correas, I.; Speicher, D. W.; Marchesi, V. T.: Structure of the
spectrin-actin binding site of erythrocyte protein 4.1. J. Biol.
Chem. 261: 13362-13366, 1986.

12. Dalla Venezia, N.; Gilsanz, F.; Alloisio, N.; Ducluzeau, M.-T.;
Benz, E. J., Jr.; Delaunay, J.: Homozygous 4.1(-) hereditary elliptocytosis
associated with a point mutation in the downstream initiation codon
of protein 4.1 gene. J. Clin. Invest. 90: 1713-1717, 1992.

13. Fairbanks, G.; Steck, T. L.; Wallach, D. F. H.: Electrophoretic
analysis of the major polypeptides of the human erythrocyte membrane. Biochemistry 10:
2606-2617, 1971.

14. Feo, C. J.; Fischer, S.; Piau, J. P.; Grange, M. J.; Tchernia,
G.: Premiere observation de l'absence d'une proteine de la membrane
erythrocytaire (bande 4-1) dans un cas d'anemie elliptocytaire familiale. Nouv.
Rev. Franc. Hemat. 22: 315-325, 1980.

15. Garbarz, M.; Devaux, I.; Bournier, O.; Grandchamp, B.; Dhermy,
D.: Protein 4.1 Lille, a novel mutation in the downstream initiation
codon of protein 4.1 gene associated with heterozygous 4,1(-) hereditary
elliptocytosis. Hum. Mutat. 5: 339-340, 1995.

16. Kan, Y.-W.: Personal Communication. San Francisco, Calif.
2/28/1986.

17. Lambert, S.; Conboy, J.; Zail, S.: A molecular study of heterozygous
protein 4.1 deficiency in hereditary elliptocytosis. Blood 72: 1926-1929,
1988.

18. Marchesi, S. L.; Conboy, J.; Agre, P.; Letsinger, J. T.; Marchesi,
V. T.; Speicher, D. W.; Mohandas, N.: Molecular analysis of insertion/deletion
mutations in protein 4.1 in elliptocytosis. I. Biochemical identification
of rearrangements in the spectrin/actin binding domain and functional
characterizations. J. Clin. Invest. 86: 516-523, 1990.

19. McGuire, M.; Smith, B. L.; Agre, P.: Distinct variants of erythrocyte
protein 4.1 inherited in linkage with elliptocytosis and Rh type in
three white families. Blood 72: 287-293, 1988.

20. Parra, M.; Gascard, P.; Walensky, L. D.; Snyder, S. H.; Mohandas,
N.; Conboy, J. G.: Cloning and characterization of 4.1G (EPB41L2),
a new member of the skeletal protein 4.1 (EPB41) gene family. Genomics 49:
298-306, 1998.

21. Ponthier, J. L.; Schluepen, C.; Chen, W.; Lersch, R. A.; Gee,
S. L.; Hou, V. C.; Lo, A. J.; Short, S. A.; Chasis, J. A.; Winkelmann,
J. C.; Conboy, J. G.: Fox-2 spicing factor binds to a conserved intron
motif to promote inclusion of protein 4.1R alternative exon 16. J.
Biol. Chem. 281: 12468-12474, 2006.

22. 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.

23. Shi, Z.-T.; Afzal, V.; Coller, B.; Patel, D.; Chasis, J. A.; Parra,
M.; Lee, G.; Paszty, C.; Stevens, M.; Walensky, L.; Peters, L. L.;
Mohandas, N.; Rubin, E.; Conboy, J. G.: Protein 4.1R-deficient mice
are viable but have erythroid membrane skeleton abnormalities. J.
Clin. Invest. 103: 331-340, 1999.

24. Takakuwa, Y.; Tchernia, G.; Rossi, M.; Benabadji, M.; Mohandas,
N.: Restoration of normal membrane stability to unstable protein
4.1-deficient erythrocyte membranes by incorporation of purified protein
4.1. J. Clin. Invest. 78: 80-85, 1986.

25. Tan, J. S.; Mohandas, N.; Conboy, J. G.: Evolutionarily conserved
coupling of transcription and alternative splicing in the EPB41 (protein
4.1R) and EPB41L3 (protein 4.1B) genes. Genomics 86: 701-707, 2005.

26. Tang, C.-J. C.; Tang, T. K.: Rapid localization of membrane skeletal
protein 4.1 (EL1) to human chromosome 1p33-p34.2 by nonradioactive
in situ hybridization. Cytogenet. Cell Genet. 57: 119, 1991.

27. Tang, T. K.; Leto, T. L.; Correas, I.; Alonso, M. A.; Marchesi,
V. T.; Benz, E. J., Jr.: Selective expression of an erythroid-specific
isoform of protein 4.1. Proc. Nat. Acad. Sci. 85: 3713-3717, 1988.

28. Tchernia, G.; Mohandas, N.; Shohet, S. B.: Deficiency of skeletal
membrane protein band 4.1 in homozygous hereditary elliptocytosis:
implications for erythrocyte membrane stability. J. Clin. Invest. 68:
454-460, 1981.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/10/2011
Patricia A. Hartz - updated: 6/30/2008
Patricia A. Hartz - updated: 2/7/2008
Victor A. McKusick - updated: 3/16/1999
Jennifer P. Macke - updated: 10/30/1998
Jennifer P. Macke - updated: 5/26/1998

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

*FIELD* ED
wwang: 05/23/2011
ckniffin: 5/10/2011
alopez: 6/30/2008
wwang: 4/23/2008
mgross: 2/20/2008
terry: 2/7/2008
terry: 5/17/2005
carol: 3/17/2004
carol: 10/31/2003
mgross: 3/10/2003
terry: 3/7/2003
kayiaros: 7/13/1999
carol: 3/17/1999
terry: 3/16/1999
dkim: 12/10/1998
alopez: 11/3/1998
alopez: 10/30/1998
dkim: 7/21/1998
alopez: 5/26/1998
joanna: 8/12/1997
mark: 3/18/1996
mark: 7/6/1995
pfoster: 10/26/1994
carol: 5/13/1994
mimadm: 4/15/1994
warfield: 4/8/1994
carol: 2/18/1993

MIM 266140
*RECORD*
*FIELD* NO
266140
*FIELD* TI
#266140 PYROPOIKILOCYTOSIS, HEREDITARY; HPP
*FIELD* TX
A number sign (#) is used with this entry because hereditary
read morepyropoikilocytosis can be caused by mutation in the alpha-spectrin
(182860) or the beta-spectrin gene (182870).

DESCRIPTION

Hereditary pyropoikilocytosis was originally described by Zarkowsky et
al. (1975) as a distinct hemolytic anemia characterized by
microspherocytosis, poikilocytosis, and an unusual thermal sensitivity
of red cells.

HPP is a subset of hereditary elliptocytosis (see 611804) due to
homozygous or compound heterozygous mutations in spectrin leading to
severe disruption of spectrin self-association (review by An and
Mohandas, 2008).

CLINICAL FEATURES

Liu et al. (1981) studied 2 patients from unrelated black families. Both
had a history of hemolytic anemia since birth (Palek et al., 1981).
Spectrin from the abnormal cells has an increased susceptibility to
thermal denaturation (Chang et al., 1979). Liu et al. (1981) concluded
that self-association of spectrin dimers into tetramers is defective,
thus accounting for the instability of red cell membrane skeletons. The
asymptomatic mothers, presumed heterozygotes, showed a mild but
reproducible increase of spectrin dimers in 0 degree C extracts and a
defective reassociation of spectrin dimers to tetramers both in solution
and in the membrane. The mothers showed normal red cell morphology and
thermal stability.

Mallouh et al. (1984) reported Saudi brother and sister with HPP. Both
parents and 8 sibs had normal red cells; 3 sibs had elliptocytosis on
peripheral blood smears.

Lecomte et al. (1987) described a Caucasian kindred in which a woman and
2 of her maternal uncles had HPP with severe hemolytic anemia, whereas
her mother and daughter had mild hereditary elliptocytosis. The
proposita's father was clinically and hematologically normal and had no
abnormality of red cell membranes. A defect in alpha-spectrin was found
in all 5 individuals. The reason for the phenotypic differences was not
clear.

MOLECULAR GENETICS

Gallagher et al. (1992) demonstrated that one of the original HPP
probands reported by Zarkowsky et al. (1975) had a substitution of
proline for leucine at position 207 of the alpha-spectrin chain (L207P;
182860.0016). By analysis of reticulocyte alpha-spectrin cDNA from one
of the HPP patients reported by Zarkowsky et al. (1975), Costa et al.
(2005) demonstrated that the non-L207P allele had a G-to-A transition at
position +5 of the donor splice site of intron 22 of the SPTA1 gene
(182860.0024).

In affected members of 2 families segregating HPP, Sahr et al. (1993)
identified homozygosity for a mutation in the SPTB gene (182870.0008).

*FIELD* SA
Knowles et al. (1983); Lawler et al. (1982); Prchal et al. (1982)
*FIELD* RF
1. An, X.; Mohandas, N.: Disorders of red cell membrane. Brit. J.
Haemat. 141: 367-375, 2008.

2. Chang, K.; Williamson, J. R.; Zarkowsky, H. S.: Effect of heat
on the circular dichroism of spectrin in hereditary pyropoikilocytosis. J.
Clin. Invest. 64: 326-328, 1979.

3. Costa, D. B.; Lozovatsky, L.; Gallagher, P. G.; Forget, B. G.:
A novel splicing mutation of the alpha-spectrin gene in the original
hereditary pyropoikilocytosis kindred. Blood 106: 4367-4369, 2005.

4. Gallagher, P. G.; Tse, W. T.; Coetzer, T.; Lecomte, M.-C.; Garbarz,
M.; Zarkowsky, H. S.; Baruchel, A.; Ballas, S. K.; Dhermy, D.; Palek,
J.; Forget, B. G.: A common type of the spectrin alpha-I 46-50a-kD
peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis
is associated with a mutation distant from the proteolytic cleavage
site: evidence for the functional importance of the triple helical
model of spectrin. J. Clin. Invest. 89: 892-898, 1992.

5. Knowles, W. J.; Morrow, J. S.; Speicher, D. W.; Zarkowsky, H. S.;
Mohandas, N.; Mentzer, W. C.; Shohet, S. B.; Marchesi, V. T.: Molecular
and functional changes in spectrin from patients with hereditary pyropoikilocytosis. J.
Clin. Invest. 71: 1867-1877, 1983.

6. Lawler, J.; Liu, S.-C.; Palek, J.; Prchal, J.: Molecular defect
of spectrin in hereditary pyropoikilocytosis: alterations in the trypsin-resistant
domain involved in spectrin self-association. J. Clin. Invest. 70:
1019-1030, 1982.

7. Lecomte, M. C.; Dhermy, D.; Garbarz, M.; Feo, C.; Gautero, H.;
Bournier, O.; Picat, C.; Chaveroche, I.; Galand, C.; Boivin, P.:
Hereditary pyropoikilocytosis and elliptocytosis in a Caucasian family:
transmission of the same molecular defect in spectrin through three
generations with different clinical expression. Hum. Genet. 77:
329-334, 1987.

8. Liu, S.-C.; Palek, J.; Prchal, J.; Castleberry, R. P.: Altered
spectrin dimer-dimer association and instability of erythrocyte membrane
skeletons in hereditary pyropoikilocytosis. J. Clin. Invest. 68:
597-605, 1981.

9. Mallouh, A.; Sa'di, A. R.; Ahmad, M. S.; Salamah, M.: Hereditary
pyropoikilocytosis: report of two cases from Saudi Arabia. Am. J.
Med. Genet. 18: 413-417, 1984.

10. Palek, J.; Liu, S. C.; Liu, P. A.; Prchal, J.; Castleberry, R.
P.: Altered assembly of spectrin in red cell membranes in hereditary
pyropoikilocytosis. Blood 57: 130-139, 1981.

11. Prchal, J.; Castleberry, R. P.; Parmley, R. T.; Crist, W. M.;
Mallouh, A.: Hereditary pyropoikilocytosis and elliptocytosis; clinical,
laboratory and ultrastructural features in infants and children. Pediat.
Res. 16: 484-489, 1982.

12. Sahr, K. E.; Coetzer, T. L.; Moy, L. S.; Derick, L. H.; Chishti,
A. H.; Jarolim, P.; Lorenzo, F.; del Giudice, E. M.; Iolascon, A.;
Gallanello, R.; Cao, A.; Delaunay, J.; Liu, S.-C.; Palek, J.: Spectrin
Cagliari: an ala-to-gly substitution in helix 1 of beta-spectrin repeat
17 that severely disrupts the structure and self-association of the
erythrocyte spectrin heterodimer. J. Biol. Chem. 268: 22656-22662,
1993.

13. Zarkowsky, H. S.; Mohandas, N.; Speaker, C. B.; Shohet, S. B.
: A congenital haemolytic anaemia with thermal sensitivity of the
erythrocyte membrane. Brit. J. Haemat. 29: 537-543, 1975.

*FIELD* CS

Heme:
Pyropoikilocytosis;
Hemolytic anemia;
Microspherocytosis;
Poikilocytosis;
Elliptocytosis

Lab:
Red cell thermal sensitivity;
Increased susceptibility of spectrin to thermal denaturation

Inheritance:
Autosomal recessive

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

*FIELD* ED
terry: 03/19/2009
carol: 3/19/2009
carol: 3/18/2009
carol: 2/18/2009
mimadm: 3/12/1994
carol: 12/16/1993
carol: 10/13/1992
carol: 5/4/1992
supermim: 3/17/1992
carol: 2/7/1992

MIM 611804
*RECORD*
*FIELD* NO
611804
*FIELD* TI
#611804 ELLIPTOCYTOSIS 1; EL1
;;ELLIPTOCYTOSIS, RHESUS-LINKED TYPE;;
PROTEIN 4.1 OF ERYTHROCYTE MEMBRANE, DEFECT OF;;
read more4.1-MINUS TRAIT;;
4.1- TRAIT
*FIELD* TX
A number sign (#) is used with this entry because elliptocytosis-1 is
caused by mutations in the gene encoding erythrocyte membrane protein
4.1 (EPB41; 130500).

Elliptocytosis-2 (130600) is caused by mutation in the SPTA1 gene
(182860), elliptocytosis-3 (see 182870) is caused by mutation in the
SPTB gene (182870), and elliptocytosis-4 (see 109270) is caused by
mutation in the SLC4A1 gene (109270).

See Delaunay (2007) for a discussion of the molecular basis of
hereditary red cell membrane disorders.

DESCRIPTION

Elliptocytosis is a hematologic disorder characterized by elliptically
shaped erythrocytes and a variable degree of hemolytic anemia. Usually
inherited as an autosomal dominant, elliptocytosis results from mutation
in any one of several genes encoding proteins of the red cell membrane
skeleton. Elliptocytosis-1 was found in the 1950s to be linked to the Rh
blood group (see 111700) and is caused by a defect in protein 4.1.

CLINICAL FEATURES

Because of the existence of at least 2 forms of elliptocytosis, one
linked to Rh and one unlinked (Morton, 1956), phenotypic differences
correlating with the differences in linkage relationships were sought.
Geerdink et al. (1967) found more hemolysis in the 'unlinked' type than
in the 'linked' type. Lux and Wolfe (1980) delineated 6 clinical
varieties of hereditary elliptocytosis (HE). Peters et al. (1966),
studying isolated red cell membranes, demonstrated an abnormality in
erythrocyte sodium transport. The extensive study of elliptocytosis in
Iceland reported by Jensson et al. (1967) showed how widely the
manifestations may vary. All cases were plausibly considered to have the
same gene. Additional evidence of heterogeneity in elliptocytosis may be
provided by the effects of combination with beta-thalassemia. Aksoy and
Erdem (1968) concluded that the combination sometimes results in mutual
enhancement, whereas in other instances it does not.

Nielsen and Strunk (1968) described a Dutch family in which, among the 7
offspring of related parents, both with elliptocytosis, 2 died in
infancy of severe anemia; a third had erythrocytes that showed more
marked morphologic changes than in heterozygotes and had severe anemia
which was compensated by splenectomy. All 3 were presumably homozygotes.
Three other sibs were heterozygotes and one was stillborn. The
elliptocytosis was of the Rh-linked variety. Lipton (1955) had reported
an instance of presumed homozygosity; both parents had elliptocytosis
without hemolysis and were second cousins. The child had hemolytic
anemia. Splenectomy was beneficial.

Early demonstrations of abnormalities of band 4.1 were provided by
Alloisio et al. (1981) and Tchernia et al. (1981). Tchernia et al.
(1981) studied a family in which 3 of 5 sisters had severe hemolytic
anemia, marked red cell fragmentation, and elliptocytic poikilocytosis.
They were presumed to be homozygotes because both parents and a
clinically unaffected (or minimally affected) sister had conventional
elliptocytosis and were probably heterozygous. The parents were
consanguineous. All 7 members of the nuclear family were Rh-identical
(Rh-negative), making linkage study impossible. Band 4.1 in the red cell
membrane proteins was markedly reduced in the 3 patients and reduced to
an intermediate level in the 3 putative heterozygotes. Thus, band 4.1 is
probably central to normal membrane stability and normal cell shape. The
critical role of protein 4.1 in red cell membrane stability was
demonstrated by the restoration of normal membrane stability with
purified protein 4.1 (Takakuwa et al., 1986).

Alloisio et al. (1982) described a heritable variant of protein 4.1 that
consists of shortening by about 75 amino acids, affecting both
subcomponents a and b and involving one or more phosphorylation sites.
The proposita was normal and was identified because of complete lack of
protein 4.1 in her son with elliptocytosis. The father had
elliptocytosis and reduced band 4.1. The son was presumably a compound
heterozygote. Homozygotes with elliptocytosis and total absence of band
4.1 were described also by Feo et al. (1980). Morle et al. (1985) gave
further information on the family reported by Alloisio et al. (1982) and
referred to the variant as protein 4.1 Presles.

Alloisio et al. (1985) suggested that the heterozygous state of this
form of hereditary elliptocytosis, called the 4.1(-) trait, results in a
characteristic clinical picture. In the course of an elliptocytosis
screening of 10 families from Southeast France and North Africa,
Alloisio et al. (1985) found 4 in which a clinically silent, dominantly
transmitted form of hereditary elliptocytosis was associated in every
case with a decrease of band 4.1. In the other families, band 4.1 was
normal, clinical signs were sometimes present, and in 3 the mode of
inheritance was uncertain. Whereas heterozygous 4.1 deficiency accounts
for one-fourth to one-third of hereditary elliptocytosis in Caucasians,
homozygosity is rare. Dalla Venezia et al. (1992) suggested that the
rarity of homozygous 4.1 deficiency is related to the severe effects on
other cell types in addition to red cells.

Dhermy et al. (1986) reported studies of 38 cases of hereditary
elliptocytosis. Fifteen patients showed a deficiency in protein 4.1. The
other 24 patients showed a spectrin self-association defect (type I HE).
A shortened spectrin beta chain was found in 1 family with a spectrin
self-association defect. All patients with the protein 4.1 deficiency
were Caucasian; most of the type I HE cases were of black extraction.

Lambert and Zail (1987) described partial deficiency of protein 4.1 as
the cause of autosomal dominant hereditary elliptocytosis. They studied
a total of 14 families, of which 1 was black, residing in South Africa.

Morle et al. (1987) described 2 sibs with severe congenital hemolytic
anemia and red cells displaying a variety of abnormal shapes. Protein
4.1 was reduced by 30%. The parents, who were consanguineous, were
devoid of any biochemical abnormality; however, their red cells were not
normal. Whether the primary defect resided in protein 4.1 was not clear.

MAPPING

On the basis of a family segregating for elliptocytosis and PGD (172200)
as well as the common polymorphisms Rh, PGM1 and alpha-fucosidase, Cook
et al. (1977) concluded that the map of 1p is, in the male,
1pter--PGD--18%--El--2%--Rh--2%--alpha-FUC--25%--PGM1--centromere. In
the female, the above intervals were estimated to be 22, 4, 2, and 37%,
respectively.

As the molecular genetics of the red cell membrane proteins advanced,
light was thrown on the early demonstration of linkage of Rh with one
form of elliptocytosis and nonlinkage with other forms. The protein 4.1
gene was mapped to chromosome 1pter-p32 (Conboy et al., 1985, 1986) by
hybridization to chromosomes sorted onto nitrocellulose filters using a
fluorescence-activated cell sorter. Studies of translocations also
localized the gene to chromosome 1pter-p32, the region of the Rh gene
(Kan, 1986). Thus, it seemed certain that the protein 4.1 gene is mutant
in Rh-linked elliptocytosis. Parra et al. (1998) stated that the EPB41
gene is located on chromosome 1p33-p32.

MOLECULAR GENETICS

Conboy et al. (1986) showed by Southern blot analysis of genomic DNA
from an Algerian family that in affected members the mutant protein 4.1
gene had a DNA rearrangement upstream from the initiation codon for
translation (130500.0001). The mRNA from the mutant gene was aberrantly
spliced.

McGuire and Agre (1987) demonstrated Rh linkage in 2 Caucasian families
with a defect in protein 4.1. In 1 family the 4.1 band showed a
reduction to about 65% of normal; in the other, a high molecular weight
4.1 was present. (A third proband had unstable 4.1.)

McGuire et al. (1988) found that variants of erythrocyte protein 4.1
were inherited in linkage with elliptocytosis and with Rh type in 3
white families. The failure of Bannerman and Renwick (1962) to find
linkage with Rh is attributable to the fact that most of their families
were black, and the defect was likely in spectrin in these families (see
182860.0003).

Partial deletion of protein 4.1 was found in 1 family with
elliptocytosis (Kan, 1986).

Lambert et al. (1988) found an elliptocytosis family in which an
apparent rearrangement of the coding region of the protein 4.1 gene led
to restriction fragment length polymorphism when DNA was tested using a
fragment of the cDNA that encompassed the coding region of the gene.

HISTORY

In a family in which both elliptocytosis and hereditary hemorrhagic
telangiectasia were segregating, Roberts (1945) pointed out that even
small bodies of data are useful for excluding close linkage. The
elliptocytosis/Rh linkage was one of the first autosomal linkages to be
demonstrated (Morton, 1956).

*FIELD* SA
Clarke et al. (1960); Garbarz et al. (1984); Kuroda et al. (1960);
Tomaselli et al. (1981)
*FIELD* RF
1. Aksoy, M.; Erdem, S.: Combination of hereditary elliptocytosis
and heterozygous beta-thalassemia: a family study. J. Med. Genet. 5:
298-301, 1968.

2. Alloisio, N.; Dorleac, E.; Delaunay, J.; Girot, R.; Galand, C.;
Boivin, P.: A shortened variant of red cell membrane protein 4.1. Blood 60:
265-267, 1982.

3. Alloisio, N.; Dorleac, E.; Girot, R.; Delaunay, J.: Analysis of
red cell membrane in a family with hereditary elliptocytosis: total
or partial absence of protein 4.1. Hum. Genet. 59: 68-71, 1981.

4. Alloisio, N.; Morle, L.; Dorleac, E.; Gentilhomme, O.; Bachir,
D.; Guetarni, D.; Colonna, P.; Bost, M.; Zouaoui, Z.; Roda, L.; Roussel,
D.; Delaunay, J.: The heterozygous form of 4.1(-) hereditary elliptocytosis
[the 4.1(-) trait]. Blood 65: 46-51, 1985.

5. Bannerman, R. M.; Renwick, J. H.: The hereditary elliptocytoses:
clinical and linkage data. Ann. Hum. Genet. 26: 23-38, 1962.

6. Clarke, C. A.; Donohoe, W. T. A.; Finn, R.; McConnell, R. B.; Sheppard,
P. M.; Nicol, D. S. H.: Data on linkage in man: ovalocytosis, sickling
and the Rhesus blood group complex. Ann. Hum. Genet. 24: 283-287,
1960.

7. Conboy, J.; Mohandas, N.; Tchernia, G.; Kan, Y. W.: Molecular
basis of hereditary elliptocytosis due to protein 4.1 deficiency. New
Eng. J. Med. 315: 680-685, 1986.

8. Conboy, J. G.; Mohandas, N.; Wang, C.; Tchernia, G.; Shohet, S.
B.; Kan, Y. W.: Molecular cloning and characterization of the gene
coding for red cell membrane skeletal protein 4.1. (Abstract) Blood 66
(suppl. 1): 31A, 1985.

9. Cook, P. J. L.; Noades, J. E.; Newton, M. S.; de Mey, R.: On the
orientation of the Rh:E1-1 linkage group. Ann. Hum. Genet. 41: 157-162,
1977.

10. Dalla Venezia, N.; Gilsanz, F.; Alloisio, N.; Ducluzeau, M.-T.;
Benz, E. J., Jr.; Delaunay, J.: Homozygous 4.1(-) hereditary elliptocytosis
associated with a point mutation in the downstream initiation codon
of protein 4.1 gene. J. Clin. Invest. 90: 1713-1717, 1992.

11. Delaunay, J.: The molecular basis of hereditary red cell membrane
disorders. Blood Rev. 21: 1-20, 2007.

12. Dhermy, D.; Garbarz, M.; Lecomte, M. C.; Feo, C.; Bournier, O.;
Chaveroche, I.; Gautero, H.; Galand, C.; Boivin, P.: Hereditary elliptocytosis:
clinical, morphological and biochemical studies of 38 cases. Nouv.
Rev. Franc. Hemat. 28: 129-140, 1986.

13. Feo, C. J.; Fischer, S.; Piau, J. P.; Grange, M. J.; Tchernia,
G.: Premiere observation de l'absence d'une proteine de la membrane
erythrocytaire (bande 4-1) dans un cas d'anemie elliptocytaire familiale. Nouv.
Rev. Franc. Hemat. 22: 315-325, 1980.

14. Garbarz, M.; Dhermy, D.; Lecomte, M. C.; Feo, C.; Chaveroche,
I.; Galand, C.; Bournier, O.; Bertrand, O.; Boivin, P.: A variant
of erythrocyte membrane skeletal protein band 4.1 associated with
hereditary elliptocytosis. Blood 64: 1006-1015, 1984.

15. Geerdink, R. A.; Nijenhuis, L. E.; Huizinga, J.: Hereditary elliptocytosis:
linkage data in man. Ann. Hum. Genet. 30: 363-378, 1967.

16. Jensson, O.; Jonasson, T.; Olafsson, O.: Hereditary elliptocytosis
in Iceland. Brit. J. Haemat. 13: 844-854, 1967.

17. Kan, Y.-W.: Personal Communication. San Francisco, Calif.
2/28/1986.

18. Kuroda, S.; Takeuchi, T.; Nagamori, H.: Data on the linkage between
elliptocytosis and Rh blood type. Jpn. J. Hum. Genet. 5: 112-118,
1960.

19. Lambert, S.; Conboy, J.; Zail, S.: A molecular study of heterozygous
protein 4.1 deficiency in hereditary elliptocytosis. Blood 72: 1926-1929,
1988.

20. Lambert, S.; Zail, S.: Partial deficiency of protein 4.1 in hereditary
elliptocytosis. Am. J. Hemat. 26: 263-272, 1987.

21. Lipton, E. L.: Elliptocytosis with hemolytic anemia: the effects
of splenectomy. Pediatrics 15: 67-82, 1955.

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

23. McGuire, M.; Agre, P.: Three distinct variants of protein 4.1
in Caucasian hereditary elliptocytosis. (Abstract) Clin. Res. 35:
428A, 1987.

24. McGuire, M.; Smith, B. L.; Agre, P.: Distinct variants of erythrocyte
protein 4.1 inherited in linkage with elliptocytosis and Rh type in
three white families. Blood 72: 287-293, 1988.

25. Morle, L.; Garbarz, M.; Alloisio, N.; Girot, R.; Chaveroche, I.;
Boivin, P.; Delaunay, J.: The characterization of protein 4.1 Presles,
a shortened variant of RBC membrane protein 4.1. Blood 65: 1511-1517,
1985.

26. Morle, L.; Pothier, B.; Alloisio, N.; Ducluzeau, M.-T.; Marques,
S.; Olim, G.; Martins e Silva, J.; Feo, C.; Garbarz, M.; Chaveroche,
I.; Boivin, P.; Delaunay, J.: Red cell membrane alteration involving
protein 4.1 and protein 3 in a case of recessively inherited haemolytic
anemia. Europ. J. Haemat. 38: 447-455, 1987.

27. 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.

28. Nielsen, J. A.; Strunk, K. W.: Homozygous hereditary elliptocytosis
as the cause of haemolytic anemia in infancy. Scand. J. Haemat. 5:
486-496, 1968.

29. Parra, M.; Gascard, P.; Walensky, L. D.; Snyder, S. H.; Mohandas,
N.; Conboy, J. G.: Cloning and characterization of 4.1G (EPB41L2),
a new member of the skeletal protein 4.1 (EPB41) gene family. Genomics 49:
298-306, 1998.

30. Peters, J. C.; Rowland, M.; Israels, L. G.; Zipursky, A.: Erythrocyte
sodium transport in hereditary elliptocytosis. Canad. J. Physiol.
Pharm. 44: 817-827, 1966.

31. Roberts, J. A. F.: Genetic linkage in man, with particular reference
to the usefulness of very small bodies of data. Quart. J. Med. 14:
27-33, 1945.

32. Takakuwa, Y.; Tchernia, G.; Rossi, M.; Benabadji, M.; Mohandas,
N.: Restoration of normal membrane stability to unstable protein
4.1-deficient erythrocyte membranes by incorporation of purified protein
4.1. J. Clin. Invest. 78: 80-85, 1986.

33. Tchernia, G.; Mohandas, N.; Shohet, S. B.: Deficiency of skeletal
membrane protein band 4.1 in homozygous hereditary elliptocytosis:
implications for erythrocyte membrane stability. J. Clin. Invest. 68:
454-460, 1981.

34. Tomaselli, M. B.; John, K. M.; Lux, S. E.: Elliptical erythrocyte
membrane skeletons and heat-sensitive spectrin in hereditary elliptocytosis. Proc.
Nat. Acad. Sci. 78: 1911-1915, 1981.

*FIELD* CD
Victor A. McKusick: 2/20/2008

*FIELD* ED
carol: 03/18/2009
carol: 3/18/2009
mgross: 2/20/2008