Full text data of LMAN1
LMAN1
(ERGIC53, F5F8D)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Protein ERGIC-53 (ER-Golgi intermediate compartment 53 kDa protein; Gp58; Intracellular mannose-specific lectin MR60; Lectin mannose-binding 1; Flags: Precursor)
Protein ERGIC-53 (ER-Golgi intermediate compartment 53 kDa protein; Gp58; Intracellular mannose-specific lectin MR60; Lectin mannose-binding 1; Flags: Precursor)
UniProt
P49257
ID LMAN1_HUMAN Reviewed; 510 AA.
AC P49257; Q12895; Q8N5I7; Q9UQG1; Q9UQG2; Q9UQG3; Q9UQG4; Q9UQG5;
read moreAC Q9UQG6; Q9UQG7; Q9UQG8; Q9UQG9; Q9UQH0; Q9UQH1; Q9UQH2;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-2002, sequence version 2.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Protein ERGIC-53;
DE AltName: Full=ER-Golgi intermediate compartment 53 kDa protein;
DE AltName: Full=Gp58;
DE AltName: Full=Intracellular mannose-specific lectin MR60;
DE AltName: Full=Lectin mannose-binding 1;
DE Flags: Precursor;
GN Name=LMAN1; Synonyms=ERGIC53, F5F8D;
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], AND PROTEIN SEQUENCE OF 31-59 AND 418-432.
RC TISSUE=Liver, and Placenta;
RX PubMed=8223692;
RA Schindler R., Itin C., Zerial M., Lottspeich F., Hauri H.-P.;
RT "ERGIC-53, a membrane protein of the ER-Golgi intermediate
RT compartment, carries an ER retention motif.";
RL Eur. J. Cell Biol. 61:1-9(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 31-41.
RC TISSUE=Peripheral blood;
RX PubMed=7876089; DOI=10.1074/jbc.270.8.3551;
RA Arar C., Carpentier V., Le Caer J.-P., Monsigny M., Legrand A.,
RA Roche A.-C.;
RT "ERGIC-53, a membrane protein of the endoplasmic reticulum-Golgi
RT intermediate compartment, is identical to MR60, an intracellular
RT mannose-specific lectin of myelomonocytic cells.";
RL J. Biol. Chem. 270:3551-3553(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-14; ALA-39 AND
RP LEU-410, AND INVOLVEMENT IN F5F8D1.
RX PubMed=10090935;
RA Nichols W.C., Terry V.H., Wheatley M.A., Yang A., Zivelin A.,
RA Ciavarella N., Stefanile C., Matsushita T., Saito H., de Bosch N.B.,
RA Ruiz-Saez A., Torres A., Thompson A.R., Feinstein D.I., White G.C.,
RA Negrier C., Vinciguerra C., Aktan M., Kaufman R.J., Ginsburg D.,
RA Seligsohn U.;
RT "ERGIC-53 gene structure and mutation analysis in 19 combined factors
RT V and VIII deficiency families.";
RL Blood 93:2261-2266(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-410.
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 [5]
RP PROTEIN SEQUENCE OF 31-44.
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 [6]
RP SIMILARITY TO LEGUMINOUS LECTINS.
RX PubMed=8205612; DOI=10.1016/0092-8674(94)90047-7;
RA Fiedler K., Simons K.;
RT "A putative novel class of animal lectins in the secretory pathway
RT homologous to leguminous lectins.";
RL Cell 77:625-626(1994).
RN [7]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line
RT protein expression map database.";
RL Proteomics 2:212-223(2002).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, MOTIF ER EXPORT,
RP AND DISULFIDE BOND.
RX PubMed=13130098; DOI=10.1242/jcs.00759;
RA Nufer O., Kappeler F., Guldbrandsen S., Hauri H.-P.;
RT "ER export of ERGIC-53 is controlled by cooperation of targeting
RT determinants in all three of its domains.";
RL J. Cell Sci. 116:4429-4440(2003).
RN [9]
RP INTERACTION WITH MCFD2, AND FUNCTION.
RX PubMed=12717434; DOI=10.1038/ng1153;
RA Zhang B., Cunningham M.A., Nichols W.C., Bernat J.A., Seligsohn U.,
RA Pipe S.W., McVey J.H., Schulte-Overberg U., de Bosch N.B.,
RA Ruiz-Saez A., White G.C., Tuddenham E.G., Kaufman R.J., Ginsburg D.;
RT "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport
RT complex.";
RL Nat. Genet. 34:220-225(2003).
RN [10]
RP SUBCELLULAR LOCATION, SUBUNIT, AND INTERCHAIN DISULFIDE BONDS.
RX PubMed=16257008; DOI=10.1016/j.jmb.2005.09.077;
RA Neve E.P., Lahtinen U., Pettersson R.F.;
RT "Oligomerization and intracellular localization of the glycoprotein
RT receptor ERGIC-53 is independent of disulfide bonds.";
RL J. Mol. Biol. 354:556-568(2005).
RN [11]
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 [12]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 32-277 IN COMPLEX WITH MCFD2
RP AND CALCIUM IONS, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=20138881; DOI=10.1016/j.febslet.2010.02.009;
RA Wigren E., Bourhis J.M., Kursula I., Guy J.E., Lindqvist Y.;
RT "Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex
RT provides insight into combined deficiency of factor V and factor
RT VIII.";
RL FEBS Lett. 584:878-882(2010).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS) OF 31-285 IN COMPLEX WITH
RP CALCIUM IONS, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=20142513; DOI=10.1073/pnas.0908526107;
RA Nishio M., Kamiya Y., Mizushima T., Wakatsuki S., Sasakawa H.,
RA Yamamoto K., Uchiyama S., Noda M., McKay A.R., Fukui K., Hauri H.P.,
RA Kato K.;
RT "Structural basis for the cooperative interplay between the two
RT causative gene products of combined factor V and factor VIII
RT deficiency.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4034-4039(2010).
CC -!- FUNCTION: Mannose-specific lectin. May recognize sugar residues of
CC glycoproteins, glycolipids, or glycosylphosphatidyl inositol
CC anchors and may be involved in the sorting or recycling of
CC proteins, lipids, or both. The LMAN1-MCFD2 complex forms a
CC specific cargo receptor for the ER-to-Golgi transport of selected
CC proteins.
CC -!- SUBUNIT: Exists both as a covalent disulfide-linked homohexamer,
CC and a complex of three disulfide-linked dimers non-covalently kept
CC together. Interacts with MCFD2.
CC -!- INTERACTION:
CC Q9BS26:ERP44; NbExp=3; IntAct=EBI-1057738, EBI-541644;
CC O15260:SURF4; NbExp=3; IntAct=EBI-1057738, EBI-1044848;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
CC compartment membrane; Single-pass type I membrane protein. Golgi
CC apparatus membrane; Single-pass membrane protein. Endoplasmic
CC reticulum membrane; Single-pass type I membrane protein.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: The FF ER export motif at the C-terminus is not sufficient
CC to support endoplasmic reticulum exit, and needs assistance of
CC Gln-501 for proper recognition of COPII coat components.
CC -!- PTM: The N-terminal may be partly blocked.
CC -!- MASS SPECTROMETRY: Mass=54222.91; Method=MALDI; Range=31-510;
CC Source=PubMed:11840567;
CC -!- DISEASE: Factor V and factor VIII combined deficiency 1 (F5F8D1)
CC [MIM:227300]: A blood coagulation disorder characterized by
CC bleeding symptoms similar to those in hemophilia or
CC parahemophilia, that are caused by single deficiency of FV or
CC FVIII, respectively. The most common symptoms are epistaxis,
CC menorrhagia, and excessive bleeding during or after trauma. Plasma
CC levels of coagulation factors V and VIII are in the range of 5 to
CC 30% of normal. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 L-type lectin-like domain.
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DR EMBL; X71661; CAA50653.1; -; mRNA.
DR EMBL; U09716; AAA95960.1; -; mRNA.
DR EMBL; AF081866; AAD32479.1; -; Genomic_DNA.
DR EMBL; AF081865; AAD32479.1; JOINED; Genomic_DNA.
DR EMBL; AF081867; AAD32480.1; -; Genomic_DNA.
DR EMBL; AF081869; AAD32481.1; -; Genomic_DNA.
DR EMBL; AF081868; AAD32481.1; JOINED; Genomic_DNA.
DR EMBL; AF081871; AAD32482.1; -; Genomic_DNA.
DR EMBL; AF081870; AAD32482.1; JOINED; Genomic_DNA.
DR EMBL; AF081873; AAD32483.1; -; Genomic_DNA.
DR EMBL; AF081872; AAD32483.1; JOINED; Genomic_DNA.
DR EMBL; AF081875; AAD32484.1; -; Genomic_DNA.
DR EMBL; AF081874; AAD32484.1; JOINED; Genomic_DNA.
DR EMBL; AF081877; AAD32485.1; -; Genomic_DNA.
DR EMBL; AF081876; AAD32485.1; JOINED; Genomic_DNA.
DR EMBL; AF081879; AAD32486.1; -; Genomic_DNA.
DR EMBL; AF081878; AAD32486.1; JOINED; Genomic_DNA.
DR EMBL; AF081880; AAD32487.1; -; Genomic_DNA.
DR EMBL; AF081882; AAD32488.1; -; Genomic_DNA.
DR EMBL; AF081881; AAD32488.1; JOINED; Genomic_DNA.
DR EMBL; AF081884; AAD32489.1; -; Genomic_DNA.
DR EMBL; AF081883; AAD32489.1; JOINED; Genomic_DNA.
DR EMBL; AF081885; AAD32490.1; -; Genomic_DNA.
DR EMBL; BC032330; AAH32330.1; -; mRNA.
DR PIR; S42626; S42626.
DR RefSeq; NP_005561.1; NM_005570.3.
DR UniGene; Hs.465295; -.
DR PDB; 3A4U; X-ray; 1.84 A; A=31-285.
DR PDB; 3LCP; X-ray; 2.45 A; A/B=32-277.
DR PDB; 4GKX; X-ray; 2.70 A; A/B/C/D/E/F=31-270.
DR PDB; 4GKY; X-ray; 2.42 A; A=31-270.
DR PDBsum; 3A4U; -.
DR PDBsum; 3LCP; -.
DR PDBsum; 4GKX; -.
DR PDBsum; 4GKY; -.
DR ProteinModelPortal; P49257; -.
DR SMR; P49257; 41-268.
DR DIP; DIP-42188N; -.
DR IntAct; P49257; 8.
DR MINT; MINT-4999949; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR PhosphoSite; P49257; -.
DR DMDM; 22261801; -.
DR PaxDb; P49257; -.
DR PeptideAtlas; P49257; -.
DR PRIDE; P49257; -.
DR DNASU; 3998; -.
DR Ensembl; ENST00000251047; ENSP00000251047; ENSG00000074695.
DR GeneID; 3998; -.
DR KEGG; hsa:3998; -.
DR UCSC; uc002lhz.3; human.
DR CTD; 3998; -.
DR GeneCards; GC18M056969; -.
DR HGNC; HGNC:6631; LMAN1.
DR HPA; HPA002320; -.
DR MIM; 227300; phenotype.
DR MIM; 601567; gene.
DR neXtProt; NX_P49257; -.
DR Orphanet; 35909; Combined deficiency of factor V and factor VIII.
DR PharmGKB; PA30399; -.
DR eggNOG; NOG292314; -.
DR HOVERGEN; HBG052332; -.
DR InParanoid; P49257; -.
DR KO; K10080; -.
DR OMA; GTVPFWA; -.
DR OrthoDB; EOG7QC7VR; -.
DR PhylomeDB; P49257; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR EvolutionaryTrace; P49257; -.
DR GeneWiki; LMAN1; -.
DR GenomeRNAi; 3998; -.
DR NextBio; 15688; -.
DR PRO; PR:P49257; -.
DR Bgee; P49257; -.
DR Genevestigator; P49257; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:ProtInc.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:ProtInc.
DR GO; GO:0016021; C:integral to membrane; TAS:ProtInc.
DR GO; GO:0030017; C:sarcomere; IEA:Ensembl.
DR GO; GO:0005537; F:mannose binding; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0051082; F:unfolded protein binding; TAS:ProtInc.
DR GO; GO:0007596; P:blood coagulation; TAS:ProtInc.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; TAS:ProtInc.
DR GO; GO:0007030; P:Golgi organization; IMP:UniProtKB.
DR GO; GO:0010638; P:positive regulation of organelle organization; IMP:UniProtKB.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006457; P:protein folding; TAS:ProtInc.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR Gene3D; 2.60.120.200; -; 1.
DR InterPro; IPR008985; ConA-like_lec_gl_sf.
DR InterPro; IPR013320; ConA-like_subgrp.
DR InterPro; IPR005052; Lectin_leg.
DR PANTHER; PTHR12223; PTHR12223; 1.
DR Pfam; PF03388; Lectin_leg-like; 1.
DR SUPFAM; SSF49899; SSF49899; 1.
DR PROSITE; PS51328; L_LECTIN_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Endoplasmic reticulum; ER-Golgi transport;
KW Golgi apparatus; Lectin; Membrane; Metal-binding; Polymorphism;
KW Protein transport; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Transport.
FT SIGNAL 1 30
FT CHAIN 31 510 Protein ERGIC-53.
FT /FTId=PRO_0000017660.
FT TOPO_DOM 31 477 Lumenal (Potential).
FT TRANSMEM 478 498 Helical; (Potential).
FT TOPO_DOM 499 510 Cytoplasmic (Potential).
FT DOMAIN 44 267 L-type lectin-like.
FT REGION 251 253 Carbohydrate binding (By similarity).
FT MOTIF 509 510 ER export motif.
FT METAL 152 152 Calcium.
FT METAL 154 154 Calcium; via carbonyl oxygen.
FT METAL 156 156 Calcium.
FT METAL 181 181 Calcium.
FT BINDING 88 88 Carbohydrate (By similarity).
FT BINDING 121 121 Carbohydrate (By similarity).
FT BINDING 156 156 Carbohydrate (By similarity).
FT BINDING 178 178 Carbohydrate (By similarity).
FT SITE 501 501 Required for ER export.
FT DISULFID 190 230
FT DISULFID 466 466 Interchain.
FT DISULFID 475 475 Interchain.
FT VARIANT 14 14 R -> Q (in dbSNP:rs1043302).
FT /FTId=VAR_013703.
FT VARIANT 39 39 V -> A (in dbSNP:rs33926449).
FT /FTId=VAR_013704.
FT VARIANT 355 355 I -> T (in dbSNP:rs3737392).
FT /FTId=VAR_049770.
FT VARIANT 410 410 M -> L (in dbSNP:rs2298711).
FT /FTId=VAR_013705.
FT CONFLICT 153 153 S -> T (in Ref. 1; CAA50653).
FT STRAND 43 46
FT HELIX 48 50
FT STRAND 52 56
FT STRAND 67 71
FT STRAND 80 83
FT STRAND 90 97
FT STRAND 102 113
FT STRAND 115 118
FT STRAND 122 130
FT STRAND 134 137
FT STRAND 145 152
FT STRAND 158 160
FT STRAND 163 172
FT HELIX 178 180
FT HELIX 183 185
FT STRAND 187 191
FT STRAND 201 208
FT STRAND 211 217
FT STRAND 219 222
FT STRAND 228 235
FT STRAND 240 249
FT STRAND 251 253
FT STRAND 256 268
SQ SEQUENCE 510 AA; 57549 MW; B87EF117C0CD386C CRC64;
MAGSRQRGLR ARVRPLFCAL LLSLGRFVRG DGVGGDPAVA LPHRRFEYKY SFKGPHLVQS
DGTVPFWAHA GNAIPSSDQI RVAPSLKSQR GSVWTKTKAA FENWEVEVTF RVTGRGRIGA
DGLAIWYAEN QGLEGPVFGS ADLWNGVGIF FDSFDNDGKK NNPAIVIIGN NGQIHYDHQN
DGASQALASC QRDFRNKPYP VRAKITYYQN TLTVMINNGF TPDKNDYEFC AKVENMIIPA
QGHFGISAAT GGLADDHDVL SFLTFQLTEP GKEPPTPDKE ISEKEKEKYQ EEFEHFQQEL
DKKKEEFQKG HPDLQGQPAE EIFESVGDRE LRQVFEGQNR IHLEIKQLNR QLDMILDEQR
RYVSSLTEEI SKRGAGMPGQ HGQITQQELD TVVKTQHEIL RQVNEMKNSM SETVRLVSGM
QHPGSAGGVY ETTQHFIDIK EHLHIVKRDI DNLVQRNMPS NEKPKCPELP PFPSCLSTVH
FIIFVVVQTV LFIGYIMYRS QQEAAAKKFF
//
ID LMAN1_HUMAN Reviewed; 510 AA.
AC P49257; Q12895; Q8N5I7; Q9UQG1; Q9UQG2; Q9UQG3; Q9UQG4; Q9UQG5;
read moreAC Q9UQG6; Q9UQG7; Q9UQG8; Q9UQG9; Q9UQH0; Q9UQH1; Q9UQH2;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-2002, sequence version 2.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Protein ERGIC-53;
DE AltName: Full=ER-Golgi intermediate compartment 53 kDa protein;
DE AltName: Full=Gp58;
DE AltName: Full=Intracellular mannose-specific lectin MR60;
DE AltName: Full=Lectin mannose-binding 1;
DE Flags: Precursor;
GN Name=LMAN1; Synonyms=ERGIC53, F5F8D;
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], AND PROTEIN SEQUENCE OF 31-59 AND 418-432.
RC TISSUE=Liver, and Placenta;
RX PubMed=8223692;
RA Schindler R., Itin C., Zerial M., Lottspeich F., Hauri H.-P.;
RT "ERGIC-53, a membrane protein of the ER-Golgi intermediate
RT compartment, carries an ER retention motif.";
RL Eur. J. Cell Biol. 61:1-9(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 31-41.
RC TISSUE=Peripheral blood;
RX PubMed=7876089; DOI=10.1074/jbc.270.8.3551;
RA Arar C., Carpentier V., Le Caer J.-P., Monsigny M., Legrand A.,
RA Roche A.-C.;
RT "ERGIC-53, a membrane protein of the endoplasmic reticulum-Golgi
RT intermediate compartment, is identical to MR60, an intracellular
RT mannose-specific lectin of myelomonocytic cells.";
RL J. Biol. Chem. 270:3551-3553(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-14; ALA-39 AND
RP LEU-410, AND INVOLVEMENT IN F5F8D1.
RX PubMed=10090935;
RA Nichols W.C., Terry V.H., Wheatley M.A., Yang A., Zivelin A.,
RA Ciavarella N., Stefanile C., Matsushita T., Saito H., de Bosch N.B.,
RA Ruiz-Saez A., Torres A., Thompson A.R., Feinstein D.I., White G.C.,
RA Negrier C., Vinciguerra C., Aktan M., Kaufman R.J., Ginsburg D.,
RA Seligsohn U.;
RT "ERGIC-53 gene structure and mutation analysis in 19 combined factors
RT V and VIII deficiency families.";
RL Blood 93:2261-2266(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-410.
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 [5]
RP PROTEIN SEQUENCE OF 31-44.
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 [6]
RP SIMILARITY TO LEGUMINOUS LECTINS.
RX PubMed=8205612; DOI=10.1016/0092-8674(94)90047-7;
RA Fiedler K., Simons K.;
RT "A putative novel class of animal lectins in the secretory pathway
RT homologous to leguminous lectins.";
RL Cell 77:625-626(1994).
RN [7]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line
RT protein expression map database.";
RL Proteomics 2:212-223(2002).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, MOTIF ER EXPORT,
RP AND DISULFIDE BOND.
RX PubMed=13130098; DOI=10.1242/jcs.00759;
RA Nufer O., Kappeler F., Guldbrandsen S., Hauri H.-P.;
RT "ER export of ERGIC-53 is controlled by cooperation of targeting
RT determinants in all three of its domains.";
RL J. Cell Sci. 116:4429-4440(2003).
RN [9]
RP INTERACTION WITH MCFD2, AND FUNCTION.
RX PubMed=12717434; DOI=10.1038/ng1153;
RA Zhang B., Cunningham M.A., Nichols W.C., Bernat J.A., Seligsohn U.,
RA Pipe S.W., McVey J.H., Schulte-Overberg U., de Bosch N.B.,
RA Ruiz-Saez A., White G.C., Tuddenham E.G., Kaufman R.J., Ginsburg D.;
RT "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport
RT complex.";
RL Nat. Genet. 34:220-225(2003).
RN [10]
RP SUBCELLULAR LOCATION, SUBUNIT, AND INTERCHAIN DISULFIDE BONDS.
RX PubMed=16257008; DOI=10.1016/j.jmb.2005.09.077;
RA Neve E.P., Lahtinen U., Pettersson R.F.;
RT "Oligomerization and intracellular localization of the glycoprotein
RT receptor ERGIC-53 is independent of disulfide bonds.";
RL J. Mol. Biol. 354:556-568(2005).
RN [11]
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 [12]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 32-277 IN COMPLEX WITH MCFD2
RP AND CALCIUM IONS, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=20138881; DOI=10.1016/j.febslet.2010.02.009;
RA Wigren E., Bourhis J.M., Kursula I., Guy J.E., Lindqvist Y.;
RT "Crystal structure of the LMAN1-CRD/MCFD2 transport receptor complex
RT provides insight into combined deficiency of factor V and factor
RT VIII.";
RL FEBS Lett. 584:878-882(2010).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS) OF 31-285 IN COMPLEX WITH
RP CALCIUM IONS, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=20142513; DOI=10.1073/pnas.0908526107;
RA Nishio M., Kamiya Y., Mizushima T., Wakatsuki S., Sasakawa H.,
RA Yamamoto K., Uchiyama S., Noda M., McKay A.R., Fukui K., Hauri H.P.,
RA Kato K.;
RT "Structural basis for the cooperative interplay between the two
RT causative gene products of combined factor V and factor VIII
RT deficiency.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4034-4039(2010).
CC -!- FUNCTION: Mannose-specific lectin. May recognize sugar residues of
CC glycoproteins, glycolipids, or glycosylphosphatidyl inositol
CC anchors and may be involved in the sorting or recycling of
CC proteins, lipids, or both. The LMAN1-MCFD2 complex forms a
CC specific cargo receptor for the ER-to-Golgi transport of selected
CC proteins.
CC -!- SUBUNIT: Exists both as a covalent disulfide-linked homohexamer,
CC and a complex of three disulfide-linked dimers non-covalently kept
CC together. Interacts with MCFD2.
CC -!- INTERACTION:
CC Q9BS26:ERP44; NbExp=3; IntAct=EBI-1057738, EBI-541644;
CC O15260:SURF4; NbExp=3; IntAct=EBI-1057738, EBI-1044848;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate
CC compartment membrane; Single-pass type I membrane protein. Golgi
CC apparatus membrane; Single-pass membrane protein. Endoplasmic
CC reticulum membrane; Single-pass type I membrane protein.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: The FF ER export motif at the C-terminus is not sufficient
CC to support endoplasmic reticulum exit, and needs assistance of
CC Gln-501 for proper recognition of COPII coat components.
CC -!- PTM: The N-terminal may be partly blocked.
CC -!- MASS SPECTROMETRY: Mass=54222.91; Method=MALDI; Range=31-510;
CC Source=PubMed:11840567;
CC -!- DISEASE: Factor V and factor VIII combined deficiency 1 (F5F8D1)
CC [MIM:227300]: A blood coagulation disorder characterized by
CC bleeding symptoms similar to those in hemophilia or
CC parahemophilia, that are caused by single deficiency of FV or
CC FVIII, respectively. The most common symptoms are epistaxis,
CC menorrhagia, and excessive bleeding during or after trauma. Plasma
CC levels of coagulation factors V and VIII are in the range of 5 to
CC 30% of normal. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 L-type lectin-like domain.
CC -----------------------------------------------------------------------
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DR EMBL; X71661; CAA50653.1; -; mRNA.
DR EMBL; U09716; AAA95960.1; -; mRNA.
DR EMBL; AF081866; AAD32479.1; -; Genomic_DNA.
DR EMBL; AF081865; AAD32479.1; JOINED; Genomic_DNA.
DR EMBL; AF081867; AAD32480.1; -; Genomic_DNA.
DR EMBL; AF081869; AAD32481.1; -; Genomic_DNA.
DR EMBL; AF081868; AAD32481.1; JOINED; Genomic_DNA.
DR EMBL; AF081871; AAD32482.1; -; Genomic_DNA.
DR EMBL; AF081870; AAD32482.1; JOINED; Genomic_DNA.
DR EMBL; AF081873; AAD32483.1; -; Genomic_DNA.
DR EMBL; AF081872; AAD32483.1; JOINED; Genomic_DNA.
DR EMBL; AF081875; AAD32484.1; -; Genomic_DNA.
DR EMBL; AF081874; AAD32484.1; JOINED; Genomic_DNA.
DR EMBL; AF081877; AAD32485.1; -; Genomic_DNA.
DR EMBL; AF081876; AAD32485.1; JOINED; Genomic_DNA.
DR EMBL; AF081879; AAD32486.1; -; Genomic_DNA.
DR EMBL; AF081878; AAD32486.1; JOINED; Genomic_DNA.
DR EMBL; AF081880; AAD32487.1; -; Genomic_DNA.
DR EMBL; AF081882; AAD32488.1; -; Genomic_DNA.
DR EMBL; AF081881; AAD32488.1; JOINED; Genomic_DNA.
DR EMBL; AF081884; AAD32489.1; -; Genomic_DNA.
DR EMBL; AF081883; AAD32489.1; JOINED; Genomic_DNA.
DR EMBL; AF081885; AAD32490.1; -; Genomic_DNA.
DR EMBL; BC032330; AAH32330.1; -; mRNA.
DR PIR; S42626; S42626.
DR RefSeq; NP_005561.1; NM_005570.3.
DR UniGene; Hs.465295; -.
DR PDB; 3A4U; X-ray; 1.84 A; A=31-285.
DR PDB; 3LCP; X-ray; 2.45 A; A/B=32-277.
DR PDB; 4GKX; X-ray; 2.70 A; A/B/C/D/E/F=31-270.
DR PDB; 4GKY; X-ray; 2.42 A; A=31-270.
DR PDBsum; 3A4U; -.
DR PDBsum; 3LCP; -.
DR PDBsum; 4GKX; -.
DR PDBsum; 4GKY; -.
DR ProteinModelPortal; P49257; -.
DR SMR; P49257; 41-268.
DR DIP; DIP-42188N; -.
DR IntAct; P49257; 8.
DR MINT; MINT-4999949; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR PhosphoSite; P49257; -.
DR DMDM; 22261801; -.
DR PaxDb; P49257; -.
DR PeptideAtlas; P49257; -.
DR PRIDE; P49257; -.
DR DNASU; 3998; -.
DR Ensembl; ENST00000251047; ENSP00000251047; ENSG00000074695.
DR GeneID; 3998; -.
DR KEGG; hsa:3998; -.
DR UCSC; uc002lhz.3; human.
DR CTD; 3998; -.
DR GeneCards; GC18M056969; -.
DR HGNC; HGNC:6631; LMAN1.
DR HPA; HPA002320; -.
DR MIM; 227300; phenotype.
DR MIM; 601567; gene.
DR neXtProt; NX_P49257; -.
DR Orphanet; 35909; Combined deficiency of factor V and factor VIII.
DR PharmGKB; PA30399; -.
DR eggNOG; NOG292314; -.
DR HOVERGEN; HBG052332; -.
DR InParanoid; P49257; -.
DR KO; K10080; -.
DR OMA; GTVPFWA; -.
DR OrthoDB; EOG7QC7VR; -.
DR PhylomeDB; P49257; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR EvolutionaryTrace; P49257; -.
DR GeneWiki; LMAN1; -.
DR GenomeRNAi; 3998; -.
DR NextBio; 15688; -.
DR PRO; PR:P49257; -.
DR Bgee; P49257; -.
DR Genevestigator; P49257; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:ProtInc.
DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:ProtInc.
DR GO; GO:0016021; C:integral to membrane; TAS:ProtInc.
DR GO; GO:0030017; C:sarcomere; IEA:Ensembl.
DR GO; GO:0005537; F:mannose binding; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0051082; F:unfolded protein binding; TAS:ProtInc.
DR GO; GO:0007596; P:blood coagulation; TAS:ProtInc.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; TAS:ProtInc.
DR GO; GO:0007030; P:Golgi organization; IMP:UniProtKB.
DR GO; GO:0010638; P:positive regulation of organelle organization; IMP:UniProtKB.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006457; P:protein folding; TAS:ProtInc.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR Gene3D; 2.60.120.200; -; 1.
DR InterPro; IPR008985; ConA-like_lec_gl_sf.
DR InterPro; IPR013320; ConA-like_subgrp.
DR InterPro; IPR005052; Lectin_leg.
DR PANTHER; PTHR12223; PTHR12223; 1.
DR Pfam; PF03388; Lectin_leg-like; 1.
DR SUPFAM; SSF49899; SSF49899; 1.
DR PROSITE; PS51328; L_LECTIN_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disulfide bond; Endoplasmic reticulum; ER-Golgi transport;
KW Golgi apparatus; Lectin; Membrane; Metal-binding; Polymorphism;
KW Protein transport; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Transport.
FT SIGNAL 1 30
FT CHAIN 31 510 Protein ERGIC-53.
FT /FTId=PRO_0000017660.
FT TOPO_DOM 31 477 Lumenal (Potential).
FT TRANSMEM 478 498 Helical; (Potential).
FT TOPO_DOM 499 510 Cytoplasmic (Potential).
FT DOMAIN 44 267 L-type lectin-like.
FT REGION 251 253 Carbohydrate binding (By similarity).
FT MOTIF 509 510 ER export motif.
FT METAL 152 152 Calcium.
FT METAL 154 154 Calcium; via carbonyl oxygen.
FT METAL 156 156 Calcium.
FT METAL 181 181 Calcium.
FT BINDING 88 88 Carbohydrate (By similarity).
FT BINDING 121 121 Carbohydrate (By similarity).
FT BINDING 156 156 Carbohydrate (By similarity).
FT BINDING 178 178 Carbohydrate (By similarity).
FT SITE 501 501 Required for ER export.
FT DISULFID 190 230
FT DISULFID 466 466 Interchain.
FT DISULFID 475 475 Interchain.
FT VARIANT 14 14 R -> Q (in dbSNP:rs1043302).
FT /FTId=VAR_013703.
FT VARIANT 39 39 V -> A (in dbSNP:rs33926449).
FT /FTId=VAR_013704.
FT VARIANT 355 355 I -> T (in dbSNP:rs3737392).
FT /FTId=VAR_049770.
FT VARIANT 410 410 M -> L (in dbSNP:rs2298711).
FT /FTId=VAR_013705.
FT CONFLICT 153 153 S -> T (in Ref. 1; CAA50653).
FT STRAND 43 46
FT HELIX 48 50
FT STRAND 52 56
FT STRAND 67 71
FT STRAND 80 83
FT STRAND 90 97
FT STRAND 102 113
FT STRAND 115 118
FT STRAND 122 130
FT STRAND 134 137
FT STRAND 145 152
FT STRAND 158 160
FT STRAND 163 172
FT HELIX 178 180
FT HELIX 183 185
FT STRAND 187 191
FT STRAND 201 208
FT STRAND 211 217
FT STRAND 219 222
FT STRAND 228 235
FT STRAND 240 249
FT STRAND 251 253
FT STRAND 256 268
SQ SEQUENCE 510 AA; 57549 MW; B87EF117C0CD386C CRC64;
MAGSRQRGLR ARVRPLFCAL LLSLGRFVRG DGVGGDPAVA LPHRRFEYKY SFKGPHLVQS
DGTVPFWAHA GNAIPSSDQI RVAPSLKSQR GSVWTKTKAA FENWEVEVTF RVTGRGRIGA
DGLAIWYAEN QGLEGPVFGS ADLWNGVGIF FDSFDNDGKK NNPAIVIIGN NGQIHYDHQN
DGASQALASC QRDFRNKPYP VRAKITYYQN TLTVMINNGF TPDKNDYEFC AKVENMIIPA
QGHFGISAAT GGLADDHDVL SFLTFQLTEP GKEPPTPDKE ISEKEKEKYQ EEFEHFQQEL
DKKKEEFQKG HPDLQGQPAE EIFESVGDRE LRQVFEGQNR IHLEIKQLNR QLDMILDEQR
RYVSSLTEEI SKRGAGMPGQ HGQITQQELD TVVKTQHEIL RQVNEMKNSM SETVRLVSGM
QHPGSAGGVY ETTQHFIDIK EHLHIVKRDI DNLVQRNMPS NEKPKCPELP PFPSCLSTVH
FIIFVVVQTV LFIGYIMYRS QQEAAAKKFF
//
MIM
227300
*RECORD*
*FIELD* NO
227300
*FIELD* TI
#227300 FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1; F5F8D1
;;FAMILIAL MULTIPLE COAGULATION FACTOR DEFICIENCY I; FMFD1;;
read moreFMFD I;;
MULTIPLE COAGULATION FACTOR DEFICIENCY I; MCFD1
*FIELD* TX
A number sign (#) is used with this entry because combined deficiency of
factor V and factor VIII type 1 can be caused by homozygous mutation in
the mannose-binding lectin-1 gene (LMAN1; 601567) on chromosome 18.
DESCRIPTION
Combined deficiency of factor V (612309) and factor VIII (300841) is
characterized by bleeding symptoms similar to those in hemophilia
(306700) or parahemophilia (227400), caused by single deficiency of FV
or FVIII, respectively. The most common symptoms are epistaxis,
menorrhagia, and excessive bleeding during or after trauma. Plasma FV
and FVIII antigen and activity levels are in the range of 5 to 30%.
Inheritance of F5F8D is autosomal recessive and distinct from the
coinheritance of FV deficiency and FVIII deficiency (summary by Zhang
and Ginsburg, 2004).
- Genetic Heterogeneity of Combined Deficiency of Factor V
and Factor VIII
Another form of combined deficiency of factor V and factor VII (F5F8D2;
613625) is caused by mutation in the MCFD2 gene (607788) on chromosome
2.
CLINICAL FEATURES
Oeri et al. (1954) presented relatively convincing laboratory data for
the existence of a combined deficiency of factors V and VIII. Affected
patients demonstrated a moderate bleeding tendency in association with
plasma levels of FV and FVIII between 5% and 30%.
Nichols et al. (1997) stated that at least 89 patients with F5F8D
belonging to 58 families had been identified.
INHERITANCE
Consanguinity in several reported families with F5F8D supported
autosomal recessive inheritance (Seibert et al., 1958; Jones et al.,
1962).
Smit Sibinga et al. (1972) studied an extensive family with combined
F5F8D. They concluded that inheritance is most likely autosomal
recessive with variable expression and partial penetrance in
heterozygotes. However, Tuddenham (1997) pointed out that heterozygotes
have normal factor V and factor VIII levels.
Cimo et al. (1977) reported an affected male whose parents were first
cousins from the northwestern coast of Spain.
POPULATION GENETICS
Seligsohn et al. (1982) counted 26 separate reported families including
those described in their report. Populations from the Mediterranean
basin accounted for most cases: Spanish, Italian, Yugoslavian, Greek,
Algerian, Oriental Jewish, and Sephardic Jewish. Ashkenazi Jews had not
been affected. Seligsohn et al. (1982) related the difference in
frequency of the disease in the 2 main branches of Jewry to historical
differences in the Diaspora. The highest frequency of F5F8D was found in
Jews of Sephardic and Middle Eastern origin living in Israel with an
estimated frequency of 1 in 100,000.
MAPPING
Nichols et al. (1997) used a positional cloning approach to identify the
gene mutant in F5F8D. Of 14 affected individuals from 8 unrelated Jewish
patients, 12 were offspring of first-cousin marriages. After a
genomewide search using 241 highly polymorphic short tandem repeat (STR)
markers, 13 of the 14 affected patients were found to be homozygous for
2 closely linked 18q markers. Patients and all available family members
were genotyped for 11 additional STRs spanning approximately 11 cM on
18q. Multipoint linkage analysis yielded a maximum lod score of 13.22.
Haplotype analysis identified a number of recombinant individuals and
established a minimum candidate interval of 2.5 cM for the gene
responsible for combined factors V and VIII deficiency. Nichols et al.
(1997) commented that the product of this locus is likely to operate at
a common step in the biosynthetic pathway for these 2 functionally and
structurally homologous coagulation proteins. Different founder
haplotypes were found in Tunisian-Jewish families and
non-Tunisian-Jewish families, indicating a split between Tunisian Jews
and other Jews of Sephardic and Middle Eastern origin. The extent of the
complete linkage disequilibrium in the Tunisian-Jewish families was at
least 6 cM and suggested that the mutation in this branch was more
recent than that in the non-Tunisian families who demonstrated complete
linkage disequilibrium over a smaller distance of less than 1.0 cM.
Neerman-Arbez et al. (1997) studied linkage of F5F8D in 17 Iranian
families with a total of 28 affected individuals. All pedigrees except 1
contained at least 1 consanguineous marriage. The report of linkage to
18q in Jewish families (Nichols et al., 1997) led them to concentrate on
markers in that region. Neerman-Arbez et al. (1997) found evidence from
informative recombinants that the F5F8D locus is situated between
D18S849 and D18S64 in an interval of approximately 3 cM. Thus, the
investigators suggested that F5F8D is genetically homogeneous in
different populations.
MOLECULAR GENETICS
Nichols et al. (1998) found that the ERGIC53 (LMAN1) gene, encoding a
component of the ER-Golgi intermediate compartment, mapped to a YAC and
BAC contig containing the critical region for the gene mutant in
combined factors V and VIII deficiency. A DNA analysis identified 2
different mutations, accounting for all affected individuals in 9
families studied. Previous studies of 9 Sephardic Jewish and Middle
Eastern Jewish families identified 2 distinct haplotypes segregating
with the disease, suggesting a possibility of 2 independent founder
chromosomes. Indeed, the 5 Sephardic Jewish families were found to be
carrying a splice donor mutation (601567.0002), whereas 9 affected
individuals in the 4 Middle Eastern Jewish families were homozygous for
a G insertion (601567.0001).
Combined with their previous reports, Zhang et al. (2006) had identified
LMAN1 or MCFD2 mutations as the cause of F5F8D in 71 of 76 families.
Among the 5 families in which no mutation was identified, 3 were due to
misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2
mutations that were missed by direct sequencing. Thus, mutations in one
or the other of these genes may account for all cases of F5F8D.
Immunoprecipitation and Western blot analysis detected a low level of
LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense
mutations in LMAN1 or MCFD2, suggesting that complete loss of the
complex may not be required for clinically significant reduction in
factor V and factor VIII.
Zhang et al. (2008) identified 5 different homozygous mutations in the
LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6
families with combined factor V and VIII deficiency. The families were
of Turkish, Iraqi, Iranian, and Italian descent.
GENOTYPE/PHENOTYPE CORRELATIONS
By reviewing available published data on 46 patients with MCFD2
mutations and 96 patients with LMAN1 mutations, Zhang et al. (2008)
found that patients with MCFD2 mutations had lower levels of both FV and
FVIII compared to those with LMAN1 mutations. Decreased plasma values
for both factors were correlated for each patient, suggesting that
deficiencies in LMAN1 or MCFD2 exert a similar impact on FV and FVIII.
In addition, platelet factor V levels were reduced to the same extent as
plasma factor V. Zhang et al. (2008) suggested that MCFD2 plays a
primary role in the export of FV and FVIII from the endoplasmic
reticulum, whereas LMAN1 plays an indirect role through its interaction
with MCFD2.
HISTORY
Marlar and Griffin (1980) identified in normal plasma a protein
inhibitor of activated protein C (PCI; 601841) and showed that this
inhibitor is deficient in combined factor V and VIII deficiency.
However, Sadler (1997) noted that deficiency of protein C inhibitor as
the basic defect in F5F8D had been excluded on several grounds.
Furthermore, Nichols et al. (1998) cited several studies documenting
normal PCI levels in patients with F5F8D and demonstrating that the
initial observation of decreased levels was due to a laboratory
artifact.
*FIELD* SA
Canfield and Kisiel (1982); Hultin and Eyster (1981); Mazzone et al.
(1982); Soff and Levin (1981)
*FIELD* RF
1. Canfield, W. M.; Kisiel, W.: Evidence of normal functional levels
of activated protein C inhibitor in combined factor V/VIII deficiency
disease. J. Clin. Invest. 70: 1260-1272, 1982.
2. Cimo, P. L.; Moake, J. L.; Ganzalez, M. J.; Natelson, E. A.; Fox,
K. R.: Inherited combined deficiency of factor V and factor VIII:
report of a case with normal factor VIII antigen and ristocetin-induced
platelet aggregation. Am. J. Path. 2: 385-391, 1977.
3. Hultin, M. B.; Eyster, M. E.: Combined factor V-VIII deficiency:
a case report with studies of factor V and VIII activation by thrombin. Blood 58:
983-985, 1981.
4. Jones, J. H.; Rizza, C. R.; Hardisty, R. M.; Dormandy, K. M.; MacPherson,
J. C.: Combined deficiency of factor V and factor VIII (antihemophilic
globulin): a report of three cases. Brit. J. Haemat. 8: 120-128,
1962.
5. Marlar, R. A.; Griffin, J. H.: Deficiency of protein C inhibitor
in combined factor V/VIII deficiency disease. J. Clin. Invest. 66:
1186-1189, 1980.
6. Mazzone, D.; Fichera, A.; Pratico, G.; Sciacca, F.: Combined congenital
deficiency of factor V and factor VIII. Acta Haemat. 68: 337-338,
1982.
7. Neerman-Arbez, M.; Antonarakis, S. E.; Blouin, J. L.; Zeinali,
S.; Akhtari, M.; Afshar, Y.; Tuddenham, E. G. D.: The locus of combined
factor V-factor VIII deficiency maps to 18q in a 3 cM interval between
D18S849 and D18S64. (Abstract) Medizinische Genetik 9: 13 only,
1997.
8. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Arnold,
N. D.; Siemieniak, D. R.; Kaufman, R. J.; Ginsburg, D.: Linkage of
combined factors V and VIII deficiency to chromosome 18q by homozygosity
mapping. J. Clin. Invest. 99: 596-601, 1997.
9. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Hertel,
C. E.; Wheatley, M. A.; Moussalli, M. J.; Hauri, H.-P.; Ciavarella,
N.; Kaufman, R. J.; Ginsburg, D.: Mutations in the ER-Golgi intermediate
compartment protein ERGIC-53 cause combined deficiency of coagulation
factors V and VIII. Cell 93: 61-70, 1998.
10. Oeri, J.; Matter, M.; Isenschmid, H.; Hauser, F.; Koller, F.:
Angeborener Mangel an Faktor V (Parahaemophilie) verbunden mit echter
Haemophilie A bei zwei Brudern. Mod. Probl. Paediatr. 1: 575-588,
1954.
11. Sadler, J. E.: Combined factors V and VIII deficiency climbs
onto the map. (Editorial) J. Clin. Invest. 99: 555-556, 1997.
12. Seibert, R. H.; Margolius, A., Jr.; Ratnoff, O. D.: Observations
on hemophilia, parahemophilia and coexistent hemophilia and parahemophilia.
Alterations in the platelets and the thromboplastin generation test. J.
Lab. Clin. Med. 52: 449-462, 1958.
13. Seligsohn, U.; Zivelin, A.; Zwang, E.: Combined factor V and
factor VIII deficiency among non-Ashkenazi Jews. New Eng. J. Med. 307:
1191-1195, 1982.
14. Smit Sibinga, C. T.; Gokemeyer, J. D. M.; ten Kate, L. P.; Bos
van Zwol, F.: Combined deficiency of factor V and factor VIII: report
of a family and genetic analysis. Brit. J. Haemat. 23: 467-481,
1972.
15. Soff, G. A.; Levin, J.: Familial multiple coagulation factor
deficiencies. I. Review of the literature: differentiation of single
hereditary disorders associated with multiple factor deficiencies
from coincidental concurrence of single factor deficiency states. Semin.
Thromb. Hemost. 7: 112-148, 1981.
16. Tuddenham, E. G. D.: Personal Communication. London, England
4/11/1997.
17. Zhang, B.; Ginsburg, D.: Familial multiple coagulation factor
deficiencies: new biologic insight from rare genetic bleeding disorders. J.
Thromb. Haemost. 2: 1564-1572, 2004.
18. Zhang, B.; McGee, B.; Yamaoka, J. S.; Guglielmone, H.; Downes,
K. A.; Minoldo, S.; Jarchum, G.; Peyvandi, F.; de Bosch, N. B.; Ruiz-Saez,
A.; Chatelain, B.; Olpinski, M.; Bockenstedt, P.; Sperl, W.; Kaufman,
R. J.; Nichols, W. C.; Tuddenham, E. G. D.; Ginsburg, D.: Combined
deficiency of factor V and factor VIII is due to mutations in either
LMAN1 or MCFD2. Blood 107: 1903-1907, 2006.
19. Zhang, B.; Spreafico, M.; Zheng, C.; Yang, A.; Platzer, P.; Callaghan,
M. U.; Avci, Z.; Ozbek, N.; Mahlangu, J.; Haw, T.; Kaufman, R. J.;
Marchant, K.; Tuddenham, E. G. D.; Seligsohn, U.; Peyvandi, F.; Ginsburg,
D.: Genotype-phenotype correlation in combined deficiency of factor
V and factor VIII. Blood 111: 5592-5600, 2008.
*FIELD* CS
Heme:
Bleeding diathesis
Lab:
Factor V deficiency;
Factor VIII deficiency
Inheritance:
Autosomal recessive
*FIELD* ED
joanna: 02/07/2011
*FIELD* CN
Carol A. Bocchini - updated: 11/3/2010
Cassandra L. Kniffin - updated: 3/10/2009
Victor A. McKusick - updated: 6/9/2006
Victor A. McKusick - updated: 5/13/2003
Victor A. McKusick - updated: 5/8/1998
Victor A. McKusick - updated: 6/19/1997
Victor A. McKusick - updated: 5/30/1997
Victor A. McKusick - updated: 4/10/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/07/2011
terry: 11/4/2010
carol: 11/3/2010
wwang: 3/19/2009
ckniffin: 3/10/2009
carol: 10/8/2008
alopez: 6/30/2006
terry: 6/9/2006
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
dkim: 12/10/1998
carol: 5/9/1998
terry: 5/8/1998
mark: 2/2/1998
terry: 1/29/1998
alopez: 6/26/1997
mark: 6/19/1997
mark: 6/2/1997
terry: 5/30/1997
mark: 4/10/1997
terry: 4/10/1997
terry: 4/3/1997
jason: 6/17/1994
davew: 6/2/1994
carol: 3/16/1993
carol: 12/7/1992
carol: 7/22/1992
supermim: 3/16/1992
*RECORD*
*FIELD* NO
227300
*FIELD* TI
#227300 FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1; F5F8D1
;;FAMILIAL MULTIPLE COAGULATION FACTOR DEFICIENCY I; FMFD1;;
read moreFMFD I;;
MULTIPLE COAGULATION FACTOR DEFICIENCY I; MCFD1
*FIELD* TX
A number sign (#) is used with this entry because combined deficiency of
factor V and factor VIII type 1 can be caused by homozygous mutation in
the mannose-binding lectin-1 gene (LMAN1; 601567) on chromosome 18.
DESCRIPTION
Combined deficiency of factor V (612309) and factor VIII (300841) is
characterized by bleeding symptoms similar to those in hemophilia
(306700) or parahemophilia (227400), caused by single deficiency of FV
or FVIII, respectively. The most common symptoms are epistaxis,
menorrhagia, and excessive bleeding during or after trauma. Plasma FV
and FVIII antigen and activity levels are in the range of 5 to 30%.
Inheritance of F5F8D is autosomal recessive and distinct from the
coinheritance of FV deficiency and FVIII deficiency (summary by Zhang
and Ginsburg, 2004).
- Genetic Heterogeneity of Combined Deficiency of Factor V
and Factor VIII
Another form of combined deficiency of factor V and factor VII (F5F8D2;
613625) is caused by mutation in the MCFD2 gene (607788) on chromosome
2.
CLINICAL FEATURES
Oeri et al. (1954) presented relatively convincing laboratory data for
the existence of a combined deficiency of factors V and VIII. Affected
patients demonstrated a moderate bleeding tendency in association with
plasma levels of FV and FVIII between 5% and 30%.
Nichols et al. (1997) stated that at least 89 patients with F5F8D
belonging to 58 families had been identified.
INHERITANCE
Consanguinity in several reported families with F5F8D supported
autosomal recessive inheritance (Seibert et al., 1958; Jones et al.,
1962).
Smit Sibinga et al. (1972) studied an extensive family with combined
F5F8D. They concluded that inheritance is most likely autosomal
recessive with variable expression and partial penetrance in
heterozygotes. However, Tuddenham (1997) pointed out that heterozygotes
have normal factor V and factor VIII levels.
Cimo et al. (1977) reported an affected male whose parents were first
cousins from the northwestern coast of Spain.
POPULATION GENETICS
Seligsohn et al. (1982) counted 26 separate reported families including
those described in their report. Populations from the Mediterranean
basin accounted for most cases: Spanish, Italian, Yugoslavian, Greek,
Algerian, Oriental Jewish, and Sephardic Jewish. Ashkenazi Jews had not
been affected. Seligsohn et al. (1982) related the difference in
frequency of the disease in the 2 main branches of Jewry to historical
differences in the Diaspora. The highest frequency of F5F8D was found in
Jews of Sephardic and Middle Eastern origin living in Israel with an
estimated frequency of 1 in 100,000.
MAPPING
Nichols et al. (1997) used a positional cloning approach to identify the
gene mutant in F5F8D. Of 14 affected individuals from 8 unrelated Jewish
patients, 12 were offspring of first-cousin marriages. After a
genomewide search using 241 highly polymorphic short tandem repeat (STR)
markers, 13 of the 14 affected patients were found to be homozygous for
2 closely linked 18q markers. Patients and all available family members
were genotyped for 11 additional STRs spanning approximately 11 cM on
18q. Multipoint linkage analysis yielded a maximum lod score of 13.22.
Haplotype analysis identified a number of recombinant individuals and
established a minimum candidate interval of 2.5 cM for the gene
responsible for combined factors V and VIII deficiency. Nichols et al.
(1997) commented that the product of this locus is likely to operate at
a common step in the biosynthetic pathway for these 2 functionally and
structurally homologous coagulation proteins. Different founder
haplotypes were found in Tunisian-Jewish families and
non-Tunisian-Jewish families, indicating a split between Tunisian Jews
and other Jews of Sephardic and Middle Eastern origin. The extent of the
complete linkage disequilibrium in the Tunisian-Jewish families was at
least 6 cM and suggested that the mutation in this branch was more
recent than that in the non-Tunisian families who demonstrated complete
linkage disequilibrium over a smaller distance of less than 1.0 cM.
Neerman-Arbez et al. (1997) studied linkage of F5F8D in 17 Iranian
families with a total of 28 affected individuals. All pedigrees except 1
contained at least 1 consanguineous marriage. The report of linkage to
18q in Jewish families (Nichols et al., 1997) led them to concentrate on
markers in that region. Neerman-Arbez et al. (1997) found evidence from
informative recombinants that the F5F8D locus is situated between
D18S849 and D18S64 in an interval of approximately 3 cM. Thus, the
investigators suggested that F5F8D is genetically homogeneous in
different populations.
MOLECULAR GENETICS
Nichols et al. (1998) found that the ERGIC53 (LMAN1) gene, encoding a
component of the ER-Golgi intermediate compartment, mapped to a YAC and
BAC contig containing the critical region for the gene mutant in
combined factors V and VIII deficiency. A DNA analysis identified 2
different mutations, accounting for all affected individuals in 9
families studied. Previous studies of 9 Sephardic Jewish and Middle
Eastern Jewish families identified 2 distinct haplotypes segregating
with the disease, suggesting a possibility of 2 independent founder
chromosomes. Indeed, the 5 Sephardic Jewish families were found to be
carrying a splice donor mutation (601567.0002), whereas 9 affected
individuals in the 4 Middle Eastern Jewish families were homozygous for
a G insertion (601567.0001).
Combined with their previous reports, Zhang et al. (2006) had identified
LMAN1 or MCFD2 mutations as the cause of F5F8D in 71 of 76 families.
Among the 5 families in which no mutation was identified, 3 were due to
misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2
mutations that were missed by direct sequencing. Thus, mutations in one
or the other of these genes may account for all cases of F5F8D.
Immunoprecipitation and Western blot analysis detected a low level of
LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense
mutations in LMAN1 or MCFD2, suggesting that complete loss of the
complex may not be required for clinically significant reduction in
factor V and factor VIII.
Zhang et al. (2008) identified 5 different homozygous mutations in the
LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6
families with combined factor V and VIII deficiency. The families were
of Turkish, Iraqi, Iranian, and Italian descent.
GENOTYPE/PHENOTYPE CORRELATIONS
By reviewing available published data on 46 patients with MCFD2
mutations and 96 patients with LMAN1 mutations, Zhang et al. (2008)
found that patients with MCFD2 mutations had lower levels of both FV and
FVIII compared to those with LMAN1 mutations. Decreased plasma values
for both factors were correlated for each patient, suggesting that
deficiencies in LMAN1 or MCFD2 exert a similar impact on FV and FVIII.
In addition, platelet factor V levels were reduced to the same extent as
plasma factor V. Zhang et al. (2008) suggested that MCFD2 plays a
primary role in the export of FV and FVIII from the endoplasmic
reticulum, whereas LMAN1 plays an indirect role through its interaction
with MCFD2.
HISTORY
Marlar and Griffin (1980) identified in normal plasma a protein
inhibitor of activated protein C (PCI; 601841) and showed that this
inhibitor is deficient in combined factor V and VIII deficiency.
However, Sadler (1997) noted that deficiency of protein C inhibitor as
the basic defect in F5F8D had been excluded on several grounds.
Furthermore, Nichols et al. (1998) cited several studies documenting
normal PCI levels in patients with F5F8D and demonstrating that the
initial observation of decreased levels was due to a laboratory
artifact.
*FIELD* SA
Canfield and Kisiel (1982); Hultin and Eyster (1981); Mazzone et al.
(1982); Soff and Levin (1981)
*FIELD* RF
1. Canfield, W. M.; Kisiel, W.: Evidence of normal functional levels
of activated protein C inhibitor in combined factor V/VIII deficiency
disease. J. Clin. Invest. 70: 1260-1272, 1982.
2. Cimo, P. L.; Moake, J. L.; Ganzalez, M. J.; Natelson, E. A.; Fox,
K. R.: Inherited combined deficiency of factor V and factor VIII:
report of a case with normal factor VIII antigen and ristocetin-induced
platelet aggregation. Am. J. Path. 2: 385-391, 1977.
3. Hultin, M. B.; Eyster, M. E.: Combined factor V-VIII deficiency:
a case report with studies of factor V and VIII activation by thrombin. Blood 58:
983-985, 1981.
4. Jones, J. H.; Rizza, C. R.; Hardisty, R. M.; Dormandy, K. M.; MacPherson,
J. C.: Combined deficiency of factor V and factor VIII (antihemophilic
globulin): a report of three cases. Brit. J. Haemat. 8: 120-128,
1962.
5. Marlar, R. A.; Griffin, J. H.: Deficiency of protein C inhibitor
in combined factor V/VIII deficiency disease. J. Clin. Invest. 66:
1186-1189, 1980.
6. Mazzone, D.; Fichera, A.; Pratico, G.; Sciacca, F.: Combined congenital
deficiency of factor V and factor VIII. Acta Haemat. 68: 337-338,
1982.
7. Neerman-Arbez, M.; Antonarakis, S. E.; Blouin, J. L.; Zeinali,
S.; Akhtari, M.; Afshar, Y.; Tuddenham, E. G. D.: The locus of combined
factor V-factor VIII deficiency maps to 18q in a 3 cM interval between
D18S849 and D18S64. (Abstract) Medizinische Genetik 9: 13 only,
1997.
8. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Arnold,
N. D.; Siemieniak, D. R.; Kaufman, R. J.; Ginsburg, D.: Linkage of
combined factors V and VIII deficiency to chromosome 18q by homozygosity
mapping. J. Clin. Invest. 99: 596-601, 1997.
9. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Hertel,
C. E.; Wheatley, M. A.; Moussalli, M. J.; Hauri, H.-P.; Ciavarella,
N.; Kaufman, R. J.; Ginsburg, D.: Mutations in the ER-Golgi intermediate
compartment protein ERGIC-53 cause combined deficiency of coagulation
factors V and VIII. Cell 93: 61-70, 1998.
10. Oeri, J.; Matter, M.; Isenschmid, H.; Hauser, F.; Koller, F.:
Angeborener Mangel an Faktor V (Parahaemophilie) verbunden mit echter
Haemophilie A bei zwei Brudern. Mod. Probl. Paediatr. 1: 575-588,
1954.
11. Sadler, J. E.: Combined factors V and VIII deficiency climbs
onto the map. (Editorial) J. Clin. Invest. 99: 555-556, 1997.
12. Seibert, R. H.; Margolius, A., Jr.; Ratnoff, O. D.: Observations
on hemophilia, parahemophilia and coexistent hemophilia and parahemophilia.
Alterations in the platelets and the thromboplastin generation test. J.
Lab. Clin. Med. 52: 449-462, 1958.
13. Seligsohn, U.; Zivelin, A.; Zwang, E.: Combined factor V and
factor VIII deficiency among non-Ashkenazi Jews. New Eng. J. Med. 307:
1191-1195, 1982.
14. Smit Sibinga, C. T.; Gokemeyer, J. D. M.; ten Kate, L. P.; Bos
van Zwol, F.: Combined deficiency of factor V and factor VIII: report
of a family and genetic analysis. Brit. J. Haemat. 23: 467-481,
1972.
15. Soff, G. A.; Levin, J.: Familial multiple coagulation factor
deficiencies. I. Review of the literature: differentiation of single
hereditary disorders associated with multiple factor deficiencies
from coincidental concurrence of single factor deficiency states. Semin.
Thromb. Hemost. 7: 112-148, 1981.
16. Tuddenham, E. G. D.: Personal Communication. London, England
4/11/1997.
17. Zhang, B.; Ginsburg, D.: Familial multiple coagulation factor
deficiencies: new biologic insight from rare genetic bleeding disorders. J.
Thromb. Haemost. 2: 1564-1572, 2004.
18. Zhang, B.; McGee, B.; Yamaoka, J. S.; Guglielmone, H.; Downes,
K. A.; Minoldo, S.; Jarchum, G.; Peyvandi, F.; de Bosch, N. B.; Ruiz-Saez,
A.; Chatelain, B.; Olpinski, M.; Bockenstedt, P.; Sperl, W.; Kaufman,
R. J.; Nichols, W. C.; Tuddenham, E. G. D.; Ginsburg, D.: Combined
deficiency of factor V and factor VIII is due to mutations in either
LMAN1 or MCFD2. Blood 107: 1903-1907, 2006.
19. Zhang, B.; Spreafico, M.; Zheng, C.; Yang, A.; Platzer, P.; Callaghan,
M. U.; Avci, Z.; Ozbek, N.; Mahlangu, J.; Haw, T.; Kaufman, R. J.;
Marchant, K.; Tuddenham, E. G. D.; Seligsohn, U.; Peyvandi, F.; Ginsburg,
D.: Genotype-phenotype correlation in combined deficiency of factor
V and factor VIII. Blood 111: 5592-5600, 2008.
*FIELD* CS
Heme:
Bleeding diathesis
Lab:
Factor V deficiency;
Factor VIII deficiency
Inheritance:
Autosomal recessive
*FIELD* ED
joanna: 02/07/2011
*FIELD* CN
Carol A. Bocchini - updated: 11/3/2010
Cassandra L. Kniffin - updated: 3/10/2009
Victor A. McKusick - updated: 6/9/2006
Victor A. McKusick - updated: 5/13/2003
Victor A. McKusick - updated: 5/8/1998
Victor A. McKusick - updated: 6/19/1997
Victor A. McKusick - updated: 5/30/1997
Victor A. McKusick - updated: 4/10/1997
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/07/2011
terry: 11/4/2010
carol: 11/3/2010
wwang: 3/19/2009
ckniffin: 3/10/2009
carol: 10/8/2008
alopez: 6/30/2006
terry: 6/9/2006
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
dkim: 12/10/1998
carol: 5/9/1998
terry: 5/8/1998
mark: 2/2/1998
terry: 1/29/1998
alopez: 6/26/1997
mark: 6/19/1997
mark: 6/2/1997
terry: 5/30/1997
mark: 4/10/1997
terry: 4/10/1997
terry: 4/3/1997
jason: 6/17/1994
davew: 6/2/1994
carol: 3/16/1993
carol: 12/7/1992
carol: 7/22/1992
supermim: 3/16/1992
MIM
601567
*RECORD*
*FIELD* NO
601567
*FIELD* TI
*601567 LECTIN, MANNOSE-BINDING, 1; LMAN1
;;INTRACELLULAR MANNOSE SPECIFIC LECTIN; MR60;;
read moreENDOPLASMIC RETICULUM-GOLGI INTERMEDIATE COMPARTMENT 53; ERGIC53
*FIELD* TX
CLONING
MR60 is a membrane mannose-specific lectin identified in intracellular
compartments of HL60 cells. MR60 is identical to ERGIC53, a protein
marker of the intermediate compartment shuttling between the endoplasmic
reticulum (ER) and the cis-Golgi apparatus whose cDNA was cloned by
Schindler et al. (1993). The 510-amino acid ERGIC53 protein has a
calculated molecular mass of 54 kD and contains a N-terminal signal
sequence, a transmembrane segment, and a short cytoplasmic domain with
an ER retention motif.
Neve et al. (2003) found that the N-terminal carbohydrate recognition
domains of ERGIC53, VIPL (LMAN2L; 609552), and VIP36 (LMAN2; 609551) are
highly conserved, particularly the motifs required for Ca(2+) and
mannose binding and the 2 cysteines predicted to be disulfide bonded.
The 3 proteins all have C-terminal ER retrieval motifs. Northern blot
analysis detected 6.0- and 2.3-kb ERGIC53 transcripts in all tissues
examined, with highest expression in skeletal muscle, kidney, liver, and
placenta.
GENE FUNCTION
The finding by Nichols et al. (1998) that mutations in ERGIC53 cause
combined factors V and VIII deficiency (F5F8D1; 227300) (see MOLECULAR
GENETICS) suggested that ERGIC53 may function as a molecular chaperone
for the transport from ER to Golgi of a specific subset of secreted
proteins, including coagulation factors V and VIII.
Nichols and Ginsburg (1999) stated that the identification of ERGIC53 as
a component of the ER-Golgi transport machinery that is required for the
efficient export of coagulation factors V and VIII was the first
demonstration of a cargo-specific pathway for protein export from the ER
in mammalian cells. However, the apparently normal levels observed in
F5F8D patients for most other plasma proteins demonstrated that ERGIC53
is not essential for the integrity of the intermediate compartment or
the more general process of protein export. Nichols and Ginsburg (1999)
suggested that the identification of the genetic defect in the subset of
patients with F5F8D but with intact ERGIC53 may unmask additional
critical components of this unique transport pathway.
Correctly folded proteins destined for secretion are packaged in the
endoplasmic reticulum into COPII-coated vesicles (Schekman and Orci,
1996), which subsequently fuse to form the endoplasmic reticulum-Golgi
intermediate compartment (ERGIC). An alternative mechanism involves
selective packaging of secreted proteins with the help of specific cargo
receptors. The latter model would be consistent with mutations in LMAN1
causing a selective block to export of factor V and factor VIII.
Approximately 30% of individuals with F5F8D have normal levels of LMAN1,
suggesting that mutations in another gene may also be associated with
F5F8D. Zhang et al. (2003) showed that inactivating mutations in the
MCFD2 gene (607788) cause F5F8D (F5F8D2; 613625) with a phenotype
indistinguishable from that caused by mutations in LMAN1. MCFD2 is
localized to the ERGIC through a direct, calcium-dependent interaction
with LMAN1. These findings suggested that a complex of MCFD2-LMAN1 forms
a specific cargo receptor for the ER-to-Golgi transport of selected
proteins, including factors V and VIII.
MAPPING
Arar et al. (1996) mapped the human LMAN1 gene by isotopic in situ
hybridization to 18q21.3-q22.
MOLECULAR GENETICS
Nichols et al. (1998) mapped the LMAN1 gene to a YAC and BAC contig
containing the critical region for combined factors V and VIII
deficiency (F5F8D1; 227300), an autosomal recessive bleeding disorder.
DNA sequence analysis identified 2 different mutations, accounting for
all affected individuals in 9 families studied. Immunofluorescence and
Western analysis of immortalized lymphocytes from patients homozygous
for either of the 2 mutations demonstrated complete lack of expression
of the mutated gene in these cells. These findings suggested that
ERGIC53 may function as a molecular chaperone for the transport from ER
to Golgi of a specific subset of secreted proteins, including
coagulation factors V and VIII.
Neerman-Arbez et al. (1999) performed SSCP and sequence analyses of the
ERGIC53 gene in 35 F5F8D families of different ethnic origins. They
identified 13 distinct mutations accounting for 52 of 70 mutant alleles.
These were 3 splice site mutations, 6 insertions and deletions resulting
in translational frameshifts, 3 nonsense codons, and elimination of the
translation initiation codon. These mutations were predicted to result
in synthesis of either a truncated protein product or no protein at all.
The study revealed that F5F8D shows extensive allelic heterogeneity and
that all ERGIC53 mutations resulting in F5F8D are 'null.' Approximately
26% of the mutations had not been identified, suggesting that lesions in
regulatory elements or severe abnormalities within the introns may be
responsible for the disease in these individuals. In 2 such families,
Neerman-Arbez et al. (1999) found that ERGIC53 protein was detectable at
normal levels in patients' lymphocytes, raising the further possibility
of defects at other genetic loci.
Nichols et al. (1999) analyzed 19 additional families by direct sequence
analysis of the entire coding region and the intron/exon junctions of
the ERGIC53 gene. Seven novel mutations were identified in 10 families,
with 1 additional family found to harbor 1 of the 2 previously described
mutations. All of the identified mutations would be predicted to result
in complete absence of functional ERGIC53 protein. In 8 of the 19
families, no mutation was identified. Genotyping data indicated that at
least 2 of these families were not linked to the ERGIC53 locus. These
results, like those of Neerman-Arbez et al. (1999), suggested that a
significant subset of combined factors V and VIII deficiency is due to
mutation in 1 or more additional genes.
Zhang et al. (2008) identified 5 different homozygous mutations in the
LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6
families with combined factor V and VIII deficiency. The families were
of Turkish, Iraqi, Iranian, and Italian descent.
*FIELD* AV
.0001
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1, MIDDLE EASTERN
JEWISH TYPE
LMAN1, 1-BP INS, 86G
Genetic linkage studies by Nichols et al. (1997) identified 2 distinct
haplotypes segregating with combined factors V and VIII deficiency
(227300), suggesting the possibility of 2 independent founder
chromosomes. Five Sephardic Jewish families shared 1 haplotype and 4
Middle Eastern Jewish families shared a different haplotype. The data
suggested that the origin of the mutation in the Middle Eastern Jewish
families may have been more ancient than that in the Sephardic Jewish
families. Nichols et al. (1998) found that the Middle Eastern Jewish
patients were homozygous for a G insertion in a run of 4 G's
corresponding to basepairs 86 to 89 of the ERGIC53 cDNA. The single
basepair insertion predicted a frameshift at codon 30, resulting in a
truncated protein containing only the first 30 N-terminal amino acids of
ERGIC53, followed by 71 residues in the new reading frame leading up to
the first stop codon. Analysis of an additional Middle Eastern Jewish
family originally from Iran, not included in the original linkage report
(Nichols et al., 1997), again identified homozygosity for the
G-insertion mutation in the affected individual, with both parents shown
to be heterozygous carriers.
.0002
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1, SEPHARDIC JEWISH
TYPE
LMAN1, IVS383DS, T-C, +2
Nichols et al. (1998) found that all 6 individuals with F5F8D (227300)
from 5 Sephardic Jewish families were homozygous for a splice donor
mutation: a thymine-to-cytosine substitution at position 2 of the intron
following codon 383, changing the highly conserved splice donor
consensus, GT to GC. Analysis of RT-PCR product in the patient was
consistent with complete failure to splice this intron. The predicted
translation product from the mutant allele contained the N-terminal 383
(of 510) amino acids of ERGIC53 followed by 18 residues encoded by the
unspliced intron leading up to the first in-frame stop codon.
.0003
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, 1-BP DEL, 795C
In 2 sibs, born of consanguineous Turkish parents, with combined factor
V and factor VIII deficiency (227300), Zhang et al. (2008) identified a
homozygous 1-bp deletion (795delC) in exon 8 of the LMAN1 gene,
resulting in a frameshift and premature termination.
.0004
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, 1-BP DEL, 1356C
In 2 affected sibs from an Iraqi Chaldean family with combined factor V
and factor VIII deficiency (227300), Zhang et al. (2008) identified a
homozygous 1-bp deletion (1356delC) in exon 11 of the LMAN1 gene,
resulting in a frameshift and premature termination.
.0005
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, MET1THR
In 2 Italian sibs with combined factor V and factor VIII deficiency
(227300), Zhang et al. (2008) identified a homozygous 2T-C transition in
the LMAN1 gene, resulting in a met1-to-thr (M1T) substitution.
*FIELD* RF
1. Arar, C.; Mignon, C.; Mattei, M.-G.; Monsigny, M.; Roche, A.-C.;
Legrand, A.: Mapping of the MR60/ERGIC-53 gene to human chromosome
18q21.3-18q22 by in situ hybridization. Mammalian Genome 7: 791-792,
1996.
2. Neerman-Arbez, M.; Johnson, K. M.; Morris, M. A.; McVey, J. H.;
Peyvandi, F.; Nichols, W. C.; Ginsburg, D.; Rossier, C.; Antonarakis,
S. E.; Tuddenham, E. G. D.: Molecular analysis of the ERGIC-53 gene
in 35 families with combined factor V-factor VIII deficiency. Blood 93:
2253-2260, 1999.
3. Neve, E. P. A.; Svensson, K.; Fuxe, J.; Petterson, R. F.: VIPL,
a VIP36-like membrane protein with a putative function in the export
of glycoproteins from the endoplasmic reticulum. Exp. Cell Res. 288:
70-83, 2003.
4. Nichols, W. C.; Ginsburg, D.: From the ER to the Golgi: insights
from the study of combined factors V and VIII deficiency. Am. J.
Hum. Genet. 64: 1493-1498, 1999.
5. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Arnold,
N. D.; Siemieniak, D. R.; Kaufman, R. J.; Ginsburg, D.: Linkage of
combined factors V and VIII deficiency to chromosome 18q by homozygosity
mapping. J. Clin. Invest. 99: 596-601, 1997.
6. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Hertel,
C. E.; Wheatley, M. A.; Moussalli, M. J.; Hauri, H.-P.; Ciavarella,
N.; Kaufman, R. J.; Ginsburg, D.: Mutations in the ER-Golgi intermediate
compartment protein ERGIC-53 cause combined deficiency of coagulation
factors V and VIII. Cell 93: 61-70, 1998.
7. Nichols, W. C.; Terry, V. H.; Wheatley, M. A.; Yang, A.; Zivelin,
A.; Ciavarella, N.; Stefanile, C.; Matsushita, T.; Saito, H.; de Bosch,
N. B.; Ruiz-Saez, A.; Torres, A.; Thompson, A. R.; Feinstein, D. I.;
White, G. C.; Negrier, C.; Vinciguerra, C.; Aktan, M.; Kaufman, R.
J.; Ginsburg, D.; Seligsohn, U.: ERGIC-53 gene structure and mutation
analysis in 19 combined factors V and VIII deficiency families. Blood 93:
2261-2266, 1999.
8. Schekman, R.; Orci, L.: Coat proteins and vesicle budding. Science 271:
1526-1533, 1996.
9. Schindler, R.; Itin, C.; Zerial, M.; Lottspeich, F.; Hauri, H.
P.: ERGIC-53, a membrane protein of the EWR-Golgi intermediate compartment,
carries an ER retention motif. Europ. J. Cell Biol. 61: 1-9, 1993.
10. Zhang, B.; Cunningham, M. A.; Nichols, W. C.; Bernat, J. A.; Seligsohn,
U.; Pipe, S. W.; McVey, J. H.; Schulte-Overberg, U.; de Bosch, N.
B.; Ruiz-Saez, A.; White, G. C.; Tuddenham, E. G. D.; Kaufman, R.
J.; Ginsburg, D.: Bleeding due to disruption of a cargo-specific
ER-to-Golgi transport complex. Nature Genet. 34: 220-225, 2003.
11. Zhang, B.; Spreafico, M.; Zheng, C.; Yang, A.; Platzer, P.; Callaghan,
M. U.; Avci, Z.; Ozbek, N.; Mahlangu, J.; Haw, T.; Kaufman, R. J.;
Marchant, K.; Tuddenham, E. G. D.; Seligsohn, U.; Peyvandi, F.; Ginsburg,
D.: Genotype-phenotype correlation in combined deficiency of factor
V and factor VIII. Blood 111: 5592-5600, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 3/10/2009
Patricia A. Hartz - updated: 8/25/2005
Victor A. McKusick - updated: 5/13/2003
Victor A. McKusick - updated: 5/28/1999
Victor A. McKusick - updated: 5/6/1999
Victor A. McKusick - updated: 5/8/1998
*FIELD* CD
Victor A. McKusick: 12/12/1996
*FIELD* ED
carol: 09/16/2013
carol: 11/3/2010
wwang: 3/19/2009
ckniffin: 3/10/2009
mgross: 8/25/2005
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
mgross: 6/7/1999
terry: 5/28/1999
carol: 5/10/1999
terry: 5/6/1999
carol: 2/9/1999
terry: 6/4/1998
carol: 5/9/1998
terry: 5/8/1998
jenny: 4/8/1997
terry: 1/17/1997
jamie: 12/18/1996
mark: 12/17/1996
jenny: 12/12/1996
mark: 12/12/1996
*RECORD*
*FIELD* NO
601567
*FIELD* TI
*601567 LECTIN, MANNOSE-BINDING, 1; LMAN1
;;INTRACELLULAR MANNOSE SPECIFIC LECTIN; MR60;;
read moreENDOPLASMIC RETICULUM-GOLGI INTERMEDIATE COMPARTMENT 53; ERGIC53
*FIELD* TX
CLONING
MR60 is a membrane mannose-specific lectin identified in intracellular
compartments of HL60 cells. MR60 is identical to ERGIC53, a protein
marker of the intermediate compartment shuttling between the endoplasmic
reticulum (ER) and the cis-Golgi apparatus whose cDNA was cloned by
Schindler et al. (1993). The 510-amino acid ERGIC53 protein has a
calculated molecular mass of 54 kD and contains a N-terminal signal
sequence, a transmembrane segment, and a short cytoplasmic domain with
an ER retention motif.
Neve et al. (2003) found that the N-terminal carbohydrate recognition
domains of ERGIC53, VIPL (LMAN2L; 609552), and VIP36 (LMAN2; 609551) are
highly conserved, particularly the motifs required for Ca(2+) and
mannose binding and the 2 cysteines predicted to be disulfide bonded.
The 3 proteins all have C-terminal ER retrieval motifs. Northern blot
analysis detected 6.0- and 2.3-kb ERGIC53 transcripts in all tissues
examined, with highest expression in skeletal muscle, kidney, liver, and
placenta.
GENE FUNCTION
The finding by Nichols et al. (1998) that mutations in ERGIC53 cause
combined factors V and VIII deficiency (F5F8D1; 227300) (see MOLECULAR
GENETICS) suggested that ERGIC53 may function as a molecular chaperone
for the transport from ER to Golgi of a specific subset of secreted
proteins, including coagulation factors V and VIII.
Nichols and Ginsburg (1999) stated that the identification of ERGIC53 as
a component of the ER-Golgi transport machinery that is required for the
efficient export of coagulation factors V and VIII was the first
demonstration of a cargo-specific pathway for protein export from the ER
in mammalian cells. However, the apparently normal levels observed in
F5F8D patients for most other plasma proteins demonstrated that ERGIC53
is not essential for the integrity of the intermediate compartment or
the more general process of protein export. Nichols and Ginsburg (1999)
suggested that the identification of the genetic defect in the subset of
patients with F5F8D but with intact ERGIC53 may unmask additional
critical components of this unique transport pathway.
Correctly folded proteins destined for secretion are packaged in the
endoplasmic reticulum into COPII-coated vesicles (Schekman and Orci,
1996), which subsequently fuse to form the endoplasmic reticulum-Golgi
intermediate compartment (ERGIC). An alternative mechanism involves
selective packaging of secreted proteins with the help of specific cargo
receptors. The latter model would be consistent with mutations in LMAN1
causing a selective block to export of factor V and factor VIII.
Approximately 30% of individuals with F5F8D have normal levels of LMAN1,
suggesting that mutations in another gene may also be associated with
F5F8D. Zhang et al. (2003) showed that inactivating mutations in the
MCFD2 gene (607788) cause F5F8D (F5F8D2; 613625) with a phenotype
indistinguishable from that caused by mutations in LMAN1. MCFD2 is
localized to the ERGIC through a direct, calcium-dependent interaction
with LMAN1. These findings suggested that a complex of MCFD2-LMAN1 forms
a specific cargo receptor for the ER-to-Golgi transport of selected
proteins, including factors V and VIII.
MAPPING
Arar et al. (1996) mapped the human LMAN1 gene by isotopic in situ
hybridization to 18q21.3-q22.
MOLECULAR GENETICS
Nichols et al. (1998) mapped the LMAN1 gene to a YAC and BAC contig
containing the critical region for combined factors V and VIII
deficiency (F5F8D1; 227300), an autosomal recessive bleeding disorder.
DNA sequence analysis identified 2 different mutations, accounting for
all affected individuals in 9 families studied. Immunofluorescence and
Western analysis of immortalized lymphocytes from patients homozygous
for either of the 2 mutations demonstrated complete lack of expression
of the mutated gene in these cells. These findings suggested that
ERGIC53 may function as a molecular chaperone for the transport from ER
to Golgi of a specific subset of secreted proteins, including
coagulation factors V and VIII.
Neerman-Arbez et al. (1999) performed SSCP and sequence analyses of the
ERGIC53 gene in 35 F5F8D families of different ethnic origins. They
identified 13 distinct mutations accounting for 52 of 70 mutant alleles.
These were 3 splice site mutations, 6 insertions and deletions resulting
in translational frameshifts, 3 nonsense codons, and elimination of the
translation initiation codon. These mutations were predicted to result
in synthesis of either a truncated protein product or no protein at all.
The study revealed that F5F8D shows extensive allelic heterogeneity and
that all ERGIC53 mutations resulting in F5F8D are 'null.' Approximately
26% of the mutations had not been identified, suggesting that lesions in
regulatory elements or severe abnormalities within the introns may be
responsible for the disease in these individuals. In 2 such families,
Neerman-Arbez et al. (1999) found that ERGIC53 protein was detectable at
normal levels in patients' lymphocytes, raising the further possibility
of defects at other genetic loci.
Nichols et al. (1999) analyzed 19 additional families by direct sequence
analysis of the entire coding region and the intron/exon junctions of
the ERGIC53 gene. Seven novel mutations were identified in 10 families,
with 1 additional family found to harbor 1 of the 2 previously described
mutations. All of the identified mutations would be predicted to result
in complete absence of functional ERGIC53 protein. In 8 of the 19
families, no mutation was identified. Genotyping data indicated that at
least 2 of these families were not linked to the ERGIC53 locus. These
results, like those of Neerman-Arbez et al. (1999), suggested that a
significant subset of combined factors V and VIII deficiency is due to
mutation in 1 or more additional genes.
Zhang et al. (2008) identified 5 different homozygous mutations in the
LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6
families with combined factor V and VIII deficiency. The families were
of Turkish, Iraqi, Iranian, and Italian descent.
*FIELD* AV
.0001
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1, MIDDLE EASTERN
JEWISH TYPE
LMAN1, 1-BP INS, 86G
Genetic linkage studies by Nichols et al. (1997) identified 2 distinct
haplotypes segregating with combined factors V and VIII deficiency
(227300), suggesting the possibility of 2 independent founder
chromosomes. Five Sephardic Jewish families shared 1 haplotype and 4
Middle Eastern Jewish families shared a different haplotype. The data
suggested that the origin of the mutation in the Middle Eastern Jewish
families may have been more ancient than that in the Sephardic Jewish
families. Nichols et al. (1998) found that the Middle Eastern Jewish
patients were homozygous for a G insertion in a run of 4 G's
corresponding to basepairs 86 to 89 of the ERGIC53 cDNA. The single
basepair insertion predicted a frameshift at codon 30, resulting in a
truncated protein containing only the first 30 N-terminal amino acids of
ERGIC53, followed by 71 residues in the new reading frame leading up to
the first stop codon. Analysis of an additional Middle Eastern Jewish
family originally from Iran, not included in the original linkage report
(Nichols et al., 1997), again identified homozygosity for the
G-insertion mutation in the affected individual, with both parents shown
to be heterozygous carriers.
.0002
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1, SEPHARDIC JEWISH
TYPE
LMAN1, IVS383DS, T-C, +2
Nichols et al. (1998) found that all 6 individuals with F5F8D (227300)
from 5 Sephardic Jewish families were homozygous for a splice donor
mutation: a thymine-to-cytosine substitution at position 2 of the intron
following codon 383, changing the highly conserved splice donor
consensus, GT to GC. Analysis of RT-PCR product in the patient was
consistent with complete failure to splice this intron. The predicted
translation product from the mutant allele contained the N-terminal 383
(of 510) amino acids of ERGIC53 followed by 18 residues encoded by the
unspliced intron leading up to the first in-frame stop codon.
.0003
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, 1-BP DEL, 795C
In 2 sibs, born of consanguineous Turkish parents, with combined factor
V and factor VIII deficiency (227300), Zhang et al. (2008) identified a
homozygous 1-bp deletion (795delC) in exon 8 of the LMAN1 gene,
resulting in a frameshift and premature termination.
.0004
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, 1-BP DEL, 1356C
In 2 affected sibs from an Iraqi Chaldean family with combined factor V
and factor VIII deficiency (227300), Zhang et al. (2008) identified a
homozygous 1-bp deletion (1356delC) in exon 11 of the LMAN1 gene,
resulting in a frameshift and premature termination.
.0005
FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, 1
LMAN1, MET1THR
In 2 Italian sibs with combined factor V and factor VIII deficiency
(227300), Zhang et al. (2008) identified a homozygous 2T-C transition in
the LMAN1 gene, resulting in a met1-to-thr (M1T) substitution.
*FIELD* RF
1. Arar, C.; Mignon, C.; Mattei, M.-G.; Monsigny, M.; Roche, A.-C.;
Legrand, A.: Mapping of the MR60/ERGIC-53 gene to human chromosome
18q21.3-18q22 by in situ hybridization. Mammalian Genome 7: 791-792,
1996.
2. Neerman-Arbez, M.; Johnson, K. M.; Morris, M. A.; McVey, J. H.;
Peyvandi, F.; Nichols, W. C.; Ginsburg, D.; Rossier, C.; Antonarakis,
S. E.; Tuddenham, E. G. D.: Molecular analysis of the ERGIC-53 gene
in 35 families with combined factor V-factor VIII deficiency. Blood 93:
2253-2260, 1999.
3. Neve, E. P. A.; Svensson, K.; Fuxe, J.; Petterson, R. F.: VIPL,
a VIP36-like membrane protein with a putative function in the export
of glycoproteins from the endoplasmic reticulum. Exp. Cell Res. 288:
70-83, 2003.
4. Nichols, W. C.; Ginsburg, D.: From the ER to the Golgi: insights
from the study of combined factors V and VIII deficiency. Am. J.
Hum. Genet. 64: 1493-1498, 1999.
5. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Arnold,
N. D.; Siemieniak, D. R.; Kaufman, R. J.; Ginsburg, D.: Linkage of
combined factors V and VIII deficiency to chromosome 18q by homozygosity
mapping. J. Clin. Invest. 99: 596-601, 1997.
6. Nichols, W. C.; Seligsohn, U.; Zivelin, A.; Terry, V. H.; Hertel,
C. E.; Wheatley, M. A.; Moussalli, M. J.; Hauri, H.-P.; Ciavarella,
N.; Kaufman, R. J.; Ginsburg, D.: Mutations in the ER-Golgi intermediate
compartment protein ERGIC-53 cause combined deficiency of coagulation
factors V and VIII. Cell 93: 61-70, 1998.
7. Nichols, W. C.; Terry, V. H.; Wheatley, M. A.; Yang, A.; Zivelin,
A.; Ciavarella, N.; Stefanile, C.; Matsushita, T.; Saito, H.; de Bosch,
N. B.; Ruiz-Saez, A.; Torres, A.; Thompson, A. R.; Feinstein, D. I.;
White, G. C.; Negrier, C.; Vinciguerra, C.; Aktan, M.; Kaufman, R.
J.; Ginsburg, D.; Seligsohn, U.: ERGIC-53 gene structure and mutation
analysis in 19 combined factors V and VIII deficiency families. Blood 93:
2261-2266, 1999.
8. Schekman, R.; Orci, L.: Coat proteins and vesicle budding. Science 271:
1526-1533, 1996.
9. Schindler, R.; Itin, C.; Zerial, M.; Lottspeich, F.; Hauri, H.
P.: ERGIC-53, a membrane protein of the EWR-Golgi intermediate compartment,
carries an ER retention motif. Europ. J. Cell Biol. 61: 1-9, 1993.
10. Zhang, B.; Cunningham, M. A.; Nichols, W. C.; Bernat, J. A.; Seligsohn,
U.; Pipe, S. W.; McVey, J. H.; Schulte-Overberg, U.; de Bosch, N.
B.; Ruiz-Saez, A.; White, G. C.; Tuddenham, E. G. D.; Kaufman, R.
J.; Ginsburg, D.: Bleeding due to disruption of a cargo-specific
ER-to-Golgi transport complex. Nature Genet. 34: 220-225, 2003.
11. Zhang, B.; Spreafico, M.; Zheng, C.; Yang, A.; Platzer, P.; Callaghan,
M. U.; Avci, Z.; Ozbek, N.; Mahlangu, J.; Haw, T.; Kaufman, R. J.;
Marchant, K.; Tuddenham, E. G. D.; Seligsohn, U.; Peyvandi, F.; Ginsburg,
D.: Genotype-phenotype correlation in combined deficiency of factor
V and factor VIII. Blood 111: 5592-5600, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 3/10/2009
Patricia A. Hartz - updated: 8/25/2005
Victor A. McKusick - updated: 5/13/2003
Victor A. McKusick - updated: 5/28/1999
Victor A. McKusick - updated: 5/6/1999
Victor A. McKusick - updated: 5/8/1998
*FIELD* CD
Victor A. McKusick: 12/12/1996
*FIELD* ED
carol: 09/16/2013
carol: 11/3/2010
wwang: 3/19/2009
ckniffin: 3/10/2009
mgross: 8/25/2005
alopez: 6/3/2003
alopez: 5/14/2003
terry: 5/13/2003
mgross: 6/7/1999
terry: 5/28/1999
carol: 5/10/1999
terry: 5/6/1999
carol: 2/9/1999
terry: 6/4/1998
carol: 5/9/1998
terry: 5/8/1998
jenny: 4/8/1997
terry: 1/17/1997
jamie: 12/18/1996
mark: 12/17/1996
jenny: 12/12/1996
mark: 12/12/1996