Full text data of GP1BB
GP1BB
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Platelet glycoprotein Ib beta chain; GP-Ib beta; GPIb-beta; GPIbB (Antigen CD42b-beta; CD42c; Flags: Precursor)
Platelet glycoprotein Ib beta chain; GP-Ib beta; GPIb-beta; GPIbB (Antigen CD42b-beta; CD42c; Flags: Precursor)
UniProt
P13224
ID GP1BB_HUMAN Reviewed; 206 AA.
AC P13224; Q14422; Q8NG40;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 1.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Platelet glycoprotein Ib beta chain;
DE Short=GP-Ib beta;
DE Short=GPIb-beta;
DE Short=GPIbB;
DE AltName: Full=Antigen CD42b-beta;
DE AltName: CD_antigen=CD42c;
DE Flags: Precursor;
GN Name=GP1BB;
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 1), AND GLYCOSYLATION AT ASN-66.
RX PubMed=3353370; DOI=10.1073/pnas.85.7.2135;
RA Lopez J.A., Chung D.W., Fujikawa K., Hagen F.S., Davie E.W.,
RA Roth G.J.;
RT "The alpha and beta chains of human platelet glycoprotein Ib are both
RT transmembrane proteins containing a leucine-rich amino acid
RT sequence.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:2135-2139(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Brain;
RX PubMed=8021244;
RA Yagi M., Edelhoff S., Disteche C.M., Roth G.J.;
RT "Structural characterization and chromosomal location of the gene
RT encoding human platelet glycoprotein Ib beta.";
RL J. Biol. Chem. 269:17424-17427(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RC TISSUE=Umbilical vein;
RX PubMed=8200976; DOI=10.1172/JCI117249;
RA Kelly M.D., Essex D.W., Shapiro S.S., Meloni F.J., Druck T.,
RA Huebner K., Konkle B.A.;
RT "Complementary DNA cloning of the alternatively expressed endothelial
RT cell glycoprotein Ib beta (GPIb beta) and localization of the GPIb
RT beta gene to chromosome 22.";
RL J. Clin. Invest. 93:2417-2424(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9022087; DOI=10.1172/JCI119188;
RA Zieger B., Hashimoto Y., Ware J.;
RT "Alternative expression of platelet glycoprotein Ib(beta) mRNA from an
RT adjacent 5' gene with an imperfect polyadenylation signal sequence.";
RL J. Clin. Invest. 99:520-525(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 11-206, AND VARIANTS BSS CYS-113
RP AND PRO-133.
RX PubMed=9116284;
RA Kunishima S., Lopez J.A., Kobayashi S., Imai N., Kamiya T., Saito H.,
RA Naoe T.;
RT "Missense mutations of the glycoprotein (GP) Ib beta gene impairing
RT the GPIb alpha/beta disulfide linkage in a family with giant platelet
RT disorder.";
RL Blood 89:2404-2412(1997).
RN [6]
RP PROTEIN SEQUENCE OF 27-40.
RX PubMed=3632685; DOI=10.1016/0006-291X(87)90963-6;
RA Canfield V.A., Ozols J., Nugent D., Roth G.J.;
RT "Isolation and characterization of the alpha and beta chains of human
RT platelet glycoprotein Ib.";
RL Biochem. Biophys. Res. Commun. 147:526-534(1987).
RN [7]
RP PROTEIN SEQUENCE OF 83-92 AND 190-200.
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 [8]
RP PHOSPHORYLATION AT SER-191, AND PROTEIN SEQUENCE OF 186-200.
RX PubMed=2504723;
RA Wardell M.R., Reynolds C.C., Berndt M.C., Wallace R.W., Fox J.E.B.;
RT "Platelet glycoprotein Ib beta is phosphorylated on serine 166 by
RT cyclic AMP-dependent protein kinase.";
RL J. Biol. Chem. 264:15656-15661(1989).
RN [9]
RP SUBUNIT, AND INTERCHAIN DISULFIDE BOND.
RX PubMed=17008541; DOI=10.1182/blood-2006-05-024091;
RA Luo S.Z., Mo X., Afshar-Kharghan V., Srinivasan S., Lopez J.A., Li R.;
RT "Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta
RT subunits in the resting platelet.";
RL Blood 109:603-609(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-191 AND THR-193, AND
RP MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION AT SER-191, AND MASS SPECTROMETRY.
RA Carrascal M., Abian J.;
RL Submitted (JAN-2008) to UniProtKB.
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.24 ANGSTROMS) OF 26-146, GLYCOSYLATION AT
RP ASN-66, AND DISULFIDE BONDS.
RX PubMed=21908432; DOI=10.1182/blood-2011-05-356253;
RA McEwan P.A., Yang W., Carr K.H., Mo X., Zheng X., Li R., Emsley J.;
RT "Quaternary organization of GPIb-IX complex and insights into Bernard-
RT Soulier syndrome revealed by the structures of GPIbbeta and a
RT GPIbbeta/GPIX chimera.";
RL Blood 118:5292-5301(2011).
CC -!- FUNCTION: Gp-Ib, a surface membrane protein of platelets,
CC participates in the formation of platelet plugs by binding to von
CC Willebrand factor, which is already bound to the subendothelium.
CC -!- SUBUNIT: Two GP-Ib beta are disulfide-linked to one GP-Ib alpha.
CC GP-IX is complexed with the GP-Ib heterodimer via a non covalent
CC linkage.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13224-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13224-2; Sequence=VSP_032671;
CC -!- TISSUE SPECIFICITY: Expressed in heart and brain.
CC -!- DISEASE: Bernard-Soulier syndrome (BSS) [MIM:231200]: A
CC coagulation disorder characterized by a prolonged bleeding time,
CC unusually large platelets, thrombocytopenia, and impaired
CC prothrombin consumption. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Platelet activation apparently involves disruption
CC of the macromolecular complex of GP-Ib with the platelet
CC glycoprotein IX (GP-IX) and dissociation of GP-Ib from the actin-
CC binding protein.
CC -!- SIMILARITY: Contains 1 LRR (leucine-rich) repeat.
CC -!- SIMILARITY: Contains 1 LRRCT domain.
CC -!- SIMILARITY: Contains 1 LRRNT domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GP1BB";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J03259; AAA52594.1; -; mRNA.
DR EMBL; AF006988; AAC39781.1; -; Genomic_DNA.
DR EMBL; L20860; AAA20398.1; -; mRNA.
DR EMBL; U59632; AAB93437.1; -; mRNA.
DR EMBL; AB086231; BAC00777.1; -; Genomic_DNA.
DR PIR; A54137; NBHUIB.
DR PIR; I55604; I55604.
DR RefSeq; NP_000398.1; NM_000407.4.
DR UniGene; Hs.283743; -.
DR UniGene; Hs.728762; -.
DR PDB; 3REZ; X-ray; 2.35 A; A/B/C/D=26-146.
DR PDB; 3RFE; X-ray; 1.24 A; A/B=26-146.
DR PDBsum; 3REZ; -.
DR PDBsum; 3RFE; -.
DR ProteinModelPortal; P13224; -.
DR SMR; P13224; 26-143.
DR IntAct; P13224; 3.
DR MINT; MINT-1530456; -.
DR STRING; 9606.ENSP00000383382; -.
DR PhosphoSite; P13224; -.
DR DMDM; 121532; -.
DR OGP; P13224; -.
DR PaxDb; P13224; -.
DR PRIDE; P13224; -.
DR DNASU; 2812; -.
DR Ensembl; ENST00000366425; ENSP00000383382; ENSG00000203618.
DR GeneID; 2812; -.
DR KEGG; hsa:2812; -.
DR UCSC; uc002zpz.2; human.
DR CTD; 2812; -.
DR GeneCards; GC22P019710; -.
DR HGNC; HGNC:4440; GP1BB.
DR MIM; 138720; gene.
DR MIM; 231200; phenotype.
DR neXtProt; NX_P13224; -.
DR Orphanet; 567; 22q11.2 deletion syndrome.
DR Orphanet; 274; Bernard-Soulier syndrome.
DR Orphanet; 853; Fetal and neonatal alloimmune thrombocytopenia.
DR PharmGKB; PA179; -.
DR eggNOG; NOG266400; -.
DR HOGENOM; HOG000060136; -.
DR HOVERGEN; HBG051791; -.
DR InParanoid; P13224; -.
DR KO; K06262; -.
DR OMA; FPPDTTE; -.
DR OrthoDB; EOG75MVZ1; -.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P13224; -.
DR GeneWiki; GP1BB; -.
DR GenomeRNAi; 2812; -.
DR NextBio; 11079; -.
DR PRO; PR:P13224; -.
DR ArrayExpress; P13224; -.
DR Genevestigator; P13224; -.
DR GO; GO:0005887; C:integral to plasma membrane; NAS:ProtInc.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:ProtInc.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; NAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; NAS:UniProtKB.
DR InterPro; IPR000483; Cys-rich_flank_reg_C.
DR InterPro; IPR000372; LRR-contain_N.
DR Pfam; PF01463; LRRCT; 1.
DR Pfam; PF01462; LRRNT; 1.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00013; LRRNT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Bernard Soulier syndrome;
KW Blood coagulation; Cell adhesion; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hemostasis; Leucine-rich repeat; Membrane;
KW Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 26
FT CHAIN 27 206 Platelet glycoprotein Ib beta chain.
FT /FTId=PRO_0000021345.
FT TOPO_DOM 27 147 Extracellular (Potential).
FT TRANSMEM 148 172 Helical; (Potential).
FT TOPO_DOM 173 206 Cytoplasmic (Potential).
FT DOMAIN 27 55 LRRNT.
FT REPEAT 60 83 LRR.
FT DOMAIN 89 143 LRRCT.
FT MOD_RES 191 191 Phosphoserine; by PKA.
FT MOD_RES 193 193 Phosphothreonine.
FT CARBOHYD 66 66 N-linked (GlcNAc...).
FT DISULFID 26 32
FT DISULFID 30 39
FT DISULFID 93 118
FT DISULFID 95 141
FT DISULFID 147 147 Interchain (with C-500 or C-501 in
FT GP1BA).
FT VAR_SEQ 1 3 MGS -> MIPSRHTMLRFLPVVNAASCPGDRRTMLVNVAAG
FT VRVLRVPLRAGGSGSLSGLRPPAIVCYLPLQRASAASGLFL
FT ARPQHCGRCGRGRGGAALSLGSPAYASRCRVSRAAVFSPWA
FT PVSLESGRAPGCSLGRPGLRGALVVWLQLGETWVRLRGDFQ
FT PACGVVRVERLAGYRDAGHQGLDGAGPAVWVLRDVAQVPAD
FT RSAYCGASLA (in isoform 2).
FT /FTId=VSP_032671.
FT VARIANT 113 113 Y -> C (in BSS).
FT /FTId=VAR_025000.
FT VARIANT 133 133 A -> P (in BSS).
FT /FTId=VAR_025001.
FT STRAND 31 33
FT STRAND 36 38
FT TURN 46 48
FT STRAND 58 61
FT TURN 72 74
FT HELIX 75 77
FT STRAND 83 85
FT HELIX 95 97
FT HELIX 98 105
FT HELIX 111 113
FT STRAND 117 121
FT TURN 122 126
FT HELIX 129 131
FT HELIX 134 139
SQ SEQUENCE 206 AA; 21718 MW; B5E81EB6F57DE0D9 CRC64;
MGSGPRGALS LLLLLLAPPS RPAAGCPAPC SCAGTLVDCG RRGLTWASLP TAFPVDTTEL
VLTGNNLTAL PPGLLDALPA LRTAHLGANP WRCDCRLVPL RAWLAGRPER APYRDLRCVA
PPALRGRLLP YLAEDELRAA CAPGPLCWGA LAAQLALLGL GLLHALLLVL LLCRLRRLRA
RARARAAARL SLTDPLVAER AGTDES
//
ID GP1BB_HUMAN Reviewed; 206 AA.
AC P13224; Q14422; Q8NG40;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 1.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Platelet glycoprotein Ib beta chain;
DE Short=GP-Ib beta;
DE Short=GPIb-beta;
DE Short=GPIbB;
DE AltName: Full=Antigen CD42b-beta;
DE AltName: CD_antigen=CD42c;
DE Flags: Precursor;
GN Name=GP1BB;
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 1), AND GLYCOSYLATION AT ASN-66.
RX PubMed=3353370; DOI=10.1073/pnas.85.7.2135;
RA Lopez J.A., Chung D.W., Fujikawa K., Hagen F.S., Davie E.W.,
RA Roth G.J.;
RT "The alpha and beta chains of human platelet glycoprotein Ib are both
RT transmembrane proteins containing a leucine-rich amino acid
RT sequence.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:2135-2139(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Brain;
RX PubMed=8021244;
RA Yagi M., Edelhoff S., Disteche C.M., Roth G.J.;
RT "Structural characterization and chromosomal location of the gene
RT encoding human platelet glycoprotein Ib beta.";
RL J. Biol. Chem. 269:17424-17427(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RC TISSUE=Umbilical vein;
RX PubMed=8200976; DOI=10.1172/JCI117249;
RA Kelly M.D., Essex D.W., Shapiro S.S., Meloni F.J., Druck T.,
RA Huebner K., Konkle B.A.;
RT "Complementary DNA cloning of the alternatively expressed endothelial
RT cell glycoprotein Ib beta (GPIb beta) and localization of the GPIb
RT beta gene to chromosome 22.";
RL J. Clin. Invest. 93:2417-2424(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9022087; DOI=10.1172/JCI119188;
RA Zieger B., Hashimoto Y., Ware J.;
RT "Alternative expression of platelet glycoprotein Ib(beta) mRNA from an
RT adjacent 5' gene with an imperfect polyadenylation signal sequence.";
RL J. Clin. Invest. 99:520-525(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 11-206, AND VARIANTS BSS CYS-113
RP AND PRO-133.
RX PubMed=9116284;
RA Kunishima S., Lopez J.A., Kobayashi S., Imai N., Kamiya T., Saito H.,
RA Naoe T.;
RT "Missense mutations of the glycoprotein (GP) Ib beta gene impairing
RT the GPIb alpha/beta disulfide linkage in a family with giant platelet
RT disorder.";
RL Blood 89:2404-2412(1997).
RN [6]
RP PROTEIN SEQUENCE OF 27-40.
RX PubMed=3632685; DOI=10.1016/0006-291X(87)90963-6;
RA Canfield V.A., Ozols J., Nugent D., Roth G.J.;
RT "Isolation and characterization of the alpha and beta chains of human
RT platelet glycoprotein Ib.";
RL Biochem. Biophys. Res. Commun. 147:526-534(1987).
RN [7]
RP PROTEIN SEQUENCE OF 83-92 AND 190-200.
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 [8]
RP PHOSPHORYLATION AT SER-191, AND PROTEIN SEQUENCE OF 186-200.
RX PubMed=2504723;
RA Wardell M.R., Reynolds C.C., Berndt M.C., Wallace R.W., Fox J.E.B.;
RT "Platelet glycoprotein Ib beta is phosphorylated on serine 166 by
RT cyclic AMP-dependent protein kinase.";
RL J. Biol. Chem. 264:15656-15661(1989).
RN [9]
RP SUBUNIT, AND INTERCHAIN DISULFIDE BOND.
RX PubMed=17008541; DOI=10.1182/blood-2006-05-024091;
RA Luo S.Z., Mo X., Afshar-Kharghan V., Srinivasan S., Lopez J.A., Li R.;
RT "Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta
RT subunits in the resting platelet.";
RL Blood 109:603-609(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-191 AND THR-193, AND
RP MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION AT SER-191, AND MASS SPECTROMETRY.
RA Carrascal M., Abian J.;
RL Submitted (JAN-2008) to UniProtKB.
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.24 ANGSTROMS) OF 26-146, GLYCOSYLATION AT
RP ASN-66, AND DISULFIDE BONDS.
RX PubMed=21908432; DOI=10.1182/blood-2011-05-356253;
RA McEwan P.A., Yang W., Carr K.H., Mo X., Zheng X., Li R., Emsley J.;
RT "Quaternary organization of GPIb-IX complex and insights into Bernard-
RT Soulier syndrome revealed by the structures of GPIbbeta and a
RT GPIbbeta/GPIX chimera.";
RL Blood 118:5292-5301(2011).
CC -!- FUNCTION: Gp-Ib, a surface membrane protein of platelets,
CC participates in the formation of platelet plugs by binding to von
CC Willebrand factor, which is already bound to the subendothelium.
CC -!- SUBUNIT: Two GP-Ib beta are disulfide-linked to one GP-Ib alpha.
CC GP-IX is complexed with the GP-Ib heterodimer via a non covalent
CC linkage.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13224-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13224-2; Sequence=VSP_032671;
CC -!- TISSUE SPECIFICITY: Expressed in heart and brain.
CC -!- DISEASE: Bernard-Soulier syndrome (BSS) [MIM:231200]: A
CC coagulation disorder characterized by a prolonged bleeding time,
CC unusually large platelets, thrombocytopenia, and impaired
CC prothrombin consumption. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Platelet activation apparently involves disruption
CC of the macromolecular complex of GP-Ib with the platelet
CC glycoprotein IX (GP-IX) and dissociation of GP-Ib from the actin-
CC binding protein.
CC -!- SIMILARITY: Contains 1 LRR (leucine-rich) repeat.
CC -!- SIMILARITY: Contains 1 LRRCT domain.
CC -!- SIMILARITY: Contains 1 LRRNT domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GP1BB";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; J03259; AAA52594.1; -; mRNA.
DR EMBL; AF006988; AAC39781.1; -; Genomic_DNA.
DR EMBL; L20860; AAA20398.1; -; mRNA.
DR EMBL; U59632; AAB93437.1; -; mRNA.
DR EMBL; AB086231; BAC00777.1; -; Genomic_DNA.
DR PIR; A54137; NBHUIB.
DR PIR; I55604; I55604.
DR RefSeq; NP_000398.1; NM_000407.4.
DR UniGene; Hs.283743; -.
DR UniGene; Hs.728762; -.
DR PDB; 3REZ; X-ray; 2.35 A; A/B/C/D=26-146.
DR PDB; 3RFE; X-ray; 1.24 A; A/B=26-146.
DR PDBsum; 3REZ; -.
DR PDBsum; 3RFE; -.
DR ProteinModelPortal; P13224; -.
DR SMR; P13224; 26-143.
DR IntAct; P13224; 3.
DR MINT; MINT-1530456; -.
DR STRING; 9606.ENSP00000383382; -.
DR PhosphoSite; P13224; -.
DR DMDM; 121532; -.
DR OGP; P13224; -.
DR PaxDb; P13224; -.
DR PRIDE; P13224; -.
DR DNASU; 2812; -.
DR Ensembl; ENST00000366425; ENSP00000383382; ENSG00000203618.
DR GeneID; 2812; -.
DR KEGG; hsa:2812; -.
DR UCSC; uc002zpz.2; human.
DR CTD; 2812; -.
DR GeneCards; GC22P019710; -.
DR HGNC; HGNC:4440; GP1BB.
DR MIM; 138720; gene.
DR MIM; 231200; phenotype.
DR neXtProt; NX_P13224; -.
DR Orphanet; 567; 22q11.2 deletion syndrome.
DR Orphanet; 274; Bernard-Soulier syndrome.
DR Orphanet; 853; Fetal and neonatal alloimmune thrombocytopenia.
DR PharmGKB; PA179; -.
DR eggNOG; NOG266400; -.
DR HOGENOM; HOG000060136; -.
DR HOVERGEN; HBG051791; -.
DR InParanoid; P13224; -.
DR KO; K06262; -.
DR OMA; FPPDTTE; -.
DR OrthoDB; EOG75MVZ1; -.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P13224; -.
DR GeneWiki; GP1BB; -.
DR GenomeRNAi; 2812; -.
DR NextBio; 11079; -.
DR PRO; PR:P13224; -.
DR ArrayExpress; P13224; -.
DR Genevestigator; P13224; -.
DR GO; GO:0005887; C:integral to plasma membrane; NAS:ProtInc.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:ProtInc.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; NAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; NAS:UniProtKB.
DR InterPro; IPR000483; Cys-rich_flank_reg_C.
DR InterPro; IPR000372; LRR-contain_N.
DR Pfam; PF01463; LRRCT; 1.
DR Pfam; PF01462; LRRNT; 1.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00013; LRRNT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Bernard Soulier syndrome;
KW Blood coagulation; Cell adhesion; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hemostasis; Leucine-rich repeat; Membrane;
KW Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 26
FT CHAIN 27 206 Platelet glycoprotein Ib beta chain.
FT /FTId=PRO_0000021345.
FT TOPO_DOM 27 147 Extracellular (Potential).
FT TRANSMEM 148 172 Helical; (Potential).
FT TOPO_DOM 173 206 Cytoplasmic (Potential).
FT DOMAIN 27 55 LRRNT.
FT REPEAT 60 83 LRR.
FT DOMAIN 89 143 LRRCT.
FT MOD_RES 191 191 Phosphoserine; by PKA.
FT MOD_RES 193 193 Phosphothreonine.
FT CARBOHYD 66 66 N-linked (GlcNAc...).
FT DISULFID 26 32
FT DISULFID 30 39
FT DISULFID 93 118
FT DISULFID 95 141
FT DISULFID 147 147 Interchain (with C-500 or C-501 in
FT GP1BA).
FT VAR_SEQ 1 3 MGS -> MIPSRHTMLRFLPVVNAASCPGDRRTMLVNVAAG
FT VRVLRVPLRAGGSGSLSGLRPPAIVCYLPLQRASAASGLFL
FT ARPQHCGRCGRGRGGAALSLGSPAYASRCRVSRAAVFSPWA
FT PVSLESGRAPGCSLGRPGLRGALVVWLQLGETWVRLRGDFQ
FT PACGVVRVERLAGYRDAGHQGLDGAGPAVWVLRDVAQVPAD
FT RSAYCGASLA (in isoform 2).
FT /FTId=VSP_032671.
FT VARIANT 113 113 Y -> C (in BSS).
FT /FTId=VAR_025000.
FT VARIANT 133 133 A -> P (in BSS).
FT /FTId=VAR_025001.
FT STRAND 31 33
FT STRAND 36 38
FT TURN 46 48
FT STRAND 58 61
FT TURN 72 74
FT HELIX 75 77
FT STRAND 83 85
FT HELIX 95 97
FT HELIX 98 105
FT HELIX 111 113
FT STRAND 117 121
FT TURN 122 126
FT HELIX 129 131
FT HELIX 134 139
SQ SEQUENCE 206 AA; 21718 MW; B5E81EB6F57DE0D9 CRC64;
MGSGPRGALS LLLLLLAPPS RPAAGCPAPC SCAGTLVDCG RRGLTWASLP TAFPVDTTEL
VLTGNNLTAL PPGLLDALPA LRTAHLGANP WRCDCRLVPL RAWLAGRPER APYRDLRCVA
PPALRGRLLP YLAEDELRAA CAPGPLCWGA LAAQLALLGL GLLHALLLVL LLCRLRRLRA
RARARAAARL SLTDPLVAER AGTDES
//
MIM
138720
*RECORD*
*FIELD* NO
138720
*FIELD* TI
*138720 GLYCOPROTEIN Ib, PLATELET, BETA POLYPEPTIDE; GP1BB
;;PLATELET GLYCOPROTEIN Ib, BETA POLYPEPTIDE;;
read moreGP Ib, BETA SUBUNIT
*FIELD* TX
DESCRIPTION
Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein that
functions as a receptor for von Willebrand factor (VWF; 613160). The
main portion of the receptor is a heterodimer composed of 2 polypeptide
chains, an alpha chain (GP1BA; 606672) and a beta chain, that are linked
by disulfide bonds. The GP1BB gene encodes the beta subunit. The
complete receptor complex includes noncovalent association of the alpha
and beta subunits with platelet glycoprotein IX (GP9; 173515) and
platelet glycoprotein V (GP5; 173511) (review by Lopez et al., 1998).
CLONING
By screening a cDNA library prepared from human erythroleukemia cells
(HEL), Lopez et al. (1988) isolated a cDNA for the beta subunit of GP
Ib. The cDNA encodes a deduced 181-amino acid protein with a molecular
mass of 22 kD. A 1-kb mRNA was detected. The beta chain contains a
single 24-amino acid leucine-rich sequence; leucine-rich sequences are
also present in the GP Ib alpha subunit, the GP IX protein, and the GP V
protein. There is a 25-amino acid transmembrane segment and a 34-amino
acid intracellular segment. The intracellular segment contains 2
potential phosphorylation sites.
Using HEL cell-derived GP1BB cDNA as a probe, Kelly et al. (1994)
detected 2 mRNA species by Northern blot analysis: a 3.5-kb species in
endothelial cells and a 1.1-kb species in HEL cells. Kelly et al. (1994)
cloned and sequenced the endothelial cell cDNA and found that it encodes
a 411-amino acid protein with a calculated molecular mass of 43 kD.
Expression of the gene was most abundant in heart and brain. The authors
concluded that the 2 mRNA species resulted from alternative expression
of the GP1BB gene in different cells.
Roth (1994), who referred to the endothelial transcript as neo-Ib-beta,
commented that this may be the first example of a nonviral gene product
being formed by starting transcription well upstream and by including a
'former' intron in the transcript. Such use of an alternative promoter
and alternative splicing of a transcript are well-known mechanisms for
generating new but related products. However, these mechanisms in
combination with a shift in reading frame and translation from a
promoter, 5-prime UTR, and intron had probably been familiar previously
only to virologists. The mechanism results in production of a new and
apparently useful protein by extending and modifying a genomic template.
Zieger et al. (1997) noted that the 206-amino acid precursor of GP
Ib-beta is synthesized from a 1.0-kb mRNA expressed by megakaryocytes,
but that a 3.5-kb transcript had been identified in other cell lines.
Zieger et al. (1997) studied the origin of the 3.5-kb transcript to
determine its relationship to the 1.0-kb mRNA. Cloning experiments
demonstrated that the longer transcript results from an imperfect
polyadenylation recognition sequence within a separate gene (SEPT9;
602724) located upstream to the platelet GP1BB gene. In the absence of
normal polyadenylation, the more 5-prime SEPT5 gene uses the
polyadenylation site within its 3-prime neighbor, the platelet GP1BB
gene.
GENE STRUCTURE
Kelly et al. (1994) reported that the coding region of the GP1BB gene is
contained within 1 exon, similar to GP1BA, GP9, and GP5.
MAPPING
Using human/hamster somatic cell hybrids, Kelly et al. (1994) localized
the GP1BB gene to chromosome 22cen-q11.2. By fluorescence in situ
hybridization, Yagi et al. (1994) regionally assigned the GP1BB gene to
22q11.2.
MOLECULAR GENETICS
Budarf et al. (1995) identified a patient with phenotypic features of
both Bernard-Soulier syndrome (BSS; 231200), a bleeding disorder, and
the velocardiofacial syndrome (VCFS; 192430). Fluorescence in situ
hybridization studies demonstrated that the patient had a deletion in
22q11.2. The patient was thrombocytopenic and had abnormal bleeding
during cardiac catheterization at the age of 18 months and circumcision
at the age of 3 years. He also bruised easily and had episodes of
epistaxis. He had large platelets on smear and diminished platelet
aggregation response to ristocetin. Studies of the patient's platelets
revealed present but decreased GP Ib-alpha and completely absent GP
Ib-beta protein. Deletion of the DiGeorge chromosomal region, resulting
in a single copy of GP1BB, was not sufficient to cause BSS, as this was
the first report of this disorder in association with VCFS. In the
patient reported by Budarf et al. (1995), Ludlow et al. (1996)
identified a mutation in the upstream promoter of the GP1BB gene
(138720.0004). Thus, in this patient, BSS resulted from deletion of 1
copy of the gene and mutation in the other copy.
Kunishima et al. (1997) described missense mutations in the GP1BB gene
(138720.0001, 138720.0002) that impaired the GP Ib alpha/beta disulfide
linkage in a family with giant platelets.
Moran et al. (2000) identified a trp21-to-ter mutation (138720.0003) in
the GP1BB gene resulting in Bernard-Soulier syndrome. Studies of
transient coexpression of this mutant, together with wildtype GP1BA and
GP9, demonstrated a failure of GP9 expression on the surface of the
testing cells. Other studies indicated that GP1BB affected the surface
expression of the complex of the GP Ib-IX complex by failing to support
the insertion of GP Ib-alpha and GP IX into the platelet membrane.
ANIMAL MODEL
Kato et al. (2004) found that Gp1bb-null mice had macrothrombocytopenia
and a severe bleeding phenotype. Electron microscropy showed increased
size of the alpha-granules compared to control alpha-granules. Western
blot analysis showed overexpression of Sept5, a gene that resides
approximately 250 nucleotides 5-prime to the Gp1bb gene and has been
associated with modulating exocytosis from neurons and platelets as part
of a presynaptic protein complex. Increased Sept5 protein levels were
seen specifically in megakaryocytes and not in brain lysates of
Gp1bb-null mice. The authors suggested that deletion of a large portion
of the Gp1bb transcript in order to create the mouse model affected
expression of the neighboring Sept5 gene. The findings unexpectedly
implicated the SEPT5 gene in the maintenance of normal alpha-granule
size, perhaps by mediating vesicle fusion.
*FIELD* AV
.0001
MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE
GP1BB, TYR88CYS
Kunishima et al. (1997) reported 2 Japanese sisters with a giant
platelet disorder that was not accompanied by thrombocytopenia or
leukocyte inclusions. During childhood, they experienced frequent
episodes of epistaxis, but thereafter the tendency to bleed settled.
Platelets from the index patient did not aggregate with ristocetin, and
she had a prolonged bleeding time (9.5 minutes, normal range 2-5
minutes). Immunoblot analysis under nonreduced conditions showed that
most of the GP Ib-alpha in the patient's platelets was not disulfide
linked with GP Ib-beta. DNA sequencing showed compound heterozygosity
for 2 independent missense mutations in the GP1BB gene: from tyr (TAC)
to cys (TGC) at residue 88, and from ala (GCC) to pro (CCC) at residue
108 (138720.0002). These mutations were thought to result in decreased
expression of the GP Ib/IX complex and to influence the association of
the complex with the membrane skeleton, consequently impairing normal
platelet morphology. The authors suggested that the phenotype caused by
mutations in the subunits of the GP Ib/IX complex could span the
spectrum from a normal phenotype, to isolated giant platelet disorder,
to a full-blown bleeding disorder such as Bernard-Soulier syndrome
(231200).
.0002
MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE
GP1BB, ALA108PRO
See 138720.0001 and Kunishima et al. (1997).
.0003
BERNARD SOULIER SYNDROME, TYPE B
GP1BB, TRP21TER
In a patient with Bernard-Soulier syndrome (231200), Moran et al. (2000)
found a G-to-A transition at nucleotide 159 of the GP1BB gene, resulting
in a premature termination of translation at amino acid trp21. The
patient was a 57-year-old Irish man with a severe bleeding diathesis.
The diagnosis of BSS was based on the presence of thrombocytopenia,
large platelets on peripheral blood smear, and a profuse bleeding
tendency requiring transfusion. Bleeding occurred both spontaneously and
after minor surgical procedures. The spontaneous bleeding apparently
stopped when the patient was about 20 years of age, but the
thrombocytopenia persisted. The patient's bleeding time was longer than
15 minutes. The patient's parents were first cousins and had no history
of abnormal bleeding. The mutation was present in homozygous form. Moran
et al. (2000) stated that this was the first report of homozygosity for
a mutation in the GP1BB gene.
.0004
BERNARD SOULIER SYNDROME, TYPE B
GP1BB, C-G, -133
In patient reported by Budarf et al. (1995) with Bernard-Soulier
syndrome (231200), velocardiofacial syndrome (192430), and a deletion in
chromosome 22q, Ludlow et al. (1996) identified a C-G transition at
position -133 in the 5-prime upstream region of the GP1BB gene,
resulting in disruption of a GATA consensus binding sequence and a
decrease in promoter activity. Thus, in this patient, BSS resulted from
deletion of 1 copy of the gene and mutation in the other copy.
*FIELD* RF
1. Budarf, M. L.; Konkle, B. A.; Ludlow, L. B.; Michaud, D.; Li, M.;
Yamashiro, D. J.; McDonald-McGinn, D.; Zackai, E. H.; Driscoll, D.
A.: Identification of a patient with Bernard-Soulier syndrome and
a deletion in the DiGeorge/velo-cardio-facial chromosomal region in
22q11.2. Hum. Molec. Genet. 4: 763-766, 1995.
2. Kato, K.; Martinez, C.; Russell, S.; Nurden, P.; Nurden, A.; Fiering,
S.; Ware, J.: Genetic deletion of mouse platelet glycoprotein Ib-beta
produces a Bernard-Soulier phenotype with increased alpha-granule
size. Blood 104: 2339-2344, 2004.
3. Kelly, M. D.; Essex, D. W.; Shapiro, S. S.; Meloni, F. J.; Druck,
T.; Huebner, K.; Konkle, B. A.: Complementary DNA cloning of the
alternatively expressed endothelial cell glycoprotein Ib-beta (GPIb-beta)
and localization of the GPIb-beta gene to chromosome 22. J. Clin.
Invest. 93: 2417-2424, 1994.
4. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya, T.;
Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
5. Lopez, J. A.; Andrews, R. K.; Afshar-Kharghan, V.; Berndt, M. C.
: Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998.
6. Lopez, J. A.; Chung, D. W.; Fujikawa, K.; Hagen, F. S.; Davie,
E. W.; Roth, G. J.: The alpha and beta chains of human platelet glycoprotein
Ib are both transmembrane proteins containing a leucine-rich amino
acid sequence. Proc. Nat. Acad. Sci. 85: 2135-2139, 1988.
7. Ludlow, L. B.; Schick, B. P.; Budarf, M. L.; Driscoll, D. A.; Zackai,
E. H.; Cohen, A.; Konkle, B. A.: Identification of a mutation in
a GATA binding site of the platelet glycoprotein Ib-beta promoter
resulting in the Bernard-Soulier syndrome. J. Biol. Chem. 271: 22076-22080,
1996.
8. Moran, N.; Morateck, P. A.; Deering, A.; Ryan, M.; Montgomery,
R. R.; Fitzgerald, D. J.; Kenny, D.: Surface expression of glycoprotein
Ib-alpha is dependent on glycoprotein Ib-beta: evidence from a novel
mutation causing Bernard-Soulier syndrome. Blood 96: 532-539, 2000.
9. Roth, G. J.: The wanderings of a platelet gene: what is 'neo'
Ib-beta telling us? (Editorial) J. Clin. Invest. 93: 2301-2302,
1994.
10. Yagi, M.; Edelhoff, S.; Disteche, C. M.; Roth, G. J.: Structural
characterization and chromosomal location of the gene encoding human
platelet glycoprotein Ib-beta. J. Biol. Chem. 269: 17424-17427,
1994.
11. Zieger, B.; Hashimoto, Y.; Ware, J.: Alternative expression of
platelet glycoprotein Ib-beta mRNA from an adjacent 5-prime gene with
an imperfect polyadenylation signal sequence. J. Clin. Invest. 99:
520-525, 1997.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/19/2009
Cassandra L. Kniffin - reorganized: 6/24/2003
Cassandra L. Kniffin - updated: 6/20/2003
Victor A. McKusick - updated: 9/28/2000
Victor A. McKusick - updated: 12/15/1999
Victor A. McKusick - updated: 12/6/1999
Victor A. McKusick - updated: 3/16/1997
*FIELD* CD
Victor A. McKusick: 1/4/1991
*FIELD* ED
carol: 10/04/2010
ckniffin: 8/31/2010
wwang: 12/10/2009
ckniffin: 11/19/2009
terry: 7/24/2003
carol: 6/24/2003
ckniffin: 6/24/2003
ckniffin: 6/20/2003
terry: 9/28/2000
alopez: 12/21/1999
terry: 12/15/1999
mgross: 12/8/1999
terry: 12/6/1999
carol: 7/13/1998
alopez: 6/16/1998
terry: 7/7/1997
mark: 3/17/1997
mark: 3/16/1997
terry: 3/10/1997
mark: 6/8/1995
jason: 7/12/1994
carol: 7/22/1993
supermim: 3/16/1992
carol: 1/8/1991
carol: 1/4/1991
*RECORD*
*FIELD* NO
138720
*FIELD* TI
*138720 GLYCOPROTEIN Ib, PLATELET, BETA POLYPEPTIDE; GP1BB
;;PLATELET GLYCOPROTEIN Ib, BETA POLYPEPTIDE;;
read moreGP Ib, BETA SUBUNIT
*FIELD* TX
DESCRIPTION
Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein that
functions as a receptor for von Willebrand factor (VWF; 613160). The
main portion of the receptor is a heterodimer composed of 2 polypeptide
chains, an alpha chain (GP1BA; 606672) and a beta chain, that are linked
by disulfide bonds. The GP1BB gene encodes the beta subunit. The
complete receptor complex includes noncovalent association of the alpha
and beta subunits with platelet glycoprotein IX (GP9; 173515) and
platelet glycoprotein V (GP5; 173511) (review by Lopez et al., 1998).
CLONING
By screening a cDNA library prepared from human erythroleukemia cells
(HEL), Lopez et al. (1988) isolated a cDNA for the beta subunit of GP
Ib. The cDNA encodes a deduced 181-amino acid protein with a molecular
mass of 22 kD. A 1-kb mRNA was detected. The beta chain contains a
single 24-amino acid leucine-rich sequence; leucine-rich sequences are
also present in the GP Ib alpha subunit, the GP IX protein, and the GP V
protein. There is a 25-amino acid transmembrane segment and a 34-amino
acid intracellular segment. The intracellular segment contains 2
potential phosphorylation sites.
Using HEL cell-derived GP1BB cDNA as a probe, Kelly et al. (1994)
detected 2 mRNA species by Northern blot analysis: a 3.5-kb species in
endothelial cells and a 1.1-kb species in HEL cells. Kelly et al. (1994)
cloned and sequenced the endothelial cell cDNA and found that it encodes
a 411-amino acid protein with a calculated molecular mass of 43 kD.
Expression of the gene was most abundant in heart and brain. The authors
concluded that the 2 mRNA species resulted from alternative expression
of the GP1BB gene in different cells.
Roth (1994), who referred to the endothelial transcript as neo-Ib-beta,
commented that this may be the first example of a nonviral gene product
being formed by starting transcription well upstream and by including a
'former' intron in the transcript. Such use of an alternative promoter
and alternative splicing of a transcript are well-known mechanisms for
generating new but related products. However, these mechanisms in
combination with a shift in reading frame and translation from a
promoter, 5-prime UTR, and intron had probably been familiar previously
only to virologists. The mechanism results in production of a new and
apparently useful protein by extending and modifying a genomic template.
Zieger et al. (1997) noted that the 206-amino acid precursor of GP
Ib-beta is synthesized from a 1.0-kb mRNA expressed by megakaryocytes,
but that a 3.5-kb transcript had been identified in other cell lines.
Zieger et al. (1997) studied the origin of the 3.5-kb transcript to
determine its relationship to the 1.0-kb mRNA. Cloning experiments
demonstrated that the longer transcript results from an imperfect
polyadenylation recognition sequence within a separate gene (SEPT9;
602724) located upstream to the platelet GP1BB gene. In the absence of
normal polyadenylation, the more 5-prime SEPT5 gene uses the
polyadenylation site within its 3-prime neighbor, the platelet GP1BB
gene.
GENE STRUCTURE
Kelly et al. (1994) reported that the coding region of the GP1BB gene is
contained within 1 exon, similar to GP1BA, GP9, and GP5.
MAPPING
Using human/hamster somatic cell hybrids, Kelly et al. (1994) localized
the GP1BB gene to chromosome 22cen-q11.2. By fluorescence in situ
hybridization, Yagi et al. (1994) regionally assigned the GP1BB gene to
22q11.2.
MOLECULAR GENETICS
Budarf et al. (1995) identified a patient with phenotypic features of
both Bernard-Soulier syndrome (BSS; 231200), a bleeding disorder, and
the velocardiofacial syndrome (VCFS; 192430). Fluorescence in situ
hybridization studies demonstrated that the patient had a deletion in
22q11.2. The patient was thrombocytopenic and had abnormal bleeding
during cardiac catheterization at the age of 18 months and circumcision
at the age of 3 years. He also bruised easily and had episodes of
epistaxis. He had large platelets on smear and diminished platelet
aggregation response to ristocetin. Studies of the patient's platelets
revealed present but decreased GP Ib-alpha and completely absent GP
Ib-beta protein. Deletion of the DiGeorge chromosomal region, resulting
in a single copy of GP1BB, was not sufficient to cause BSS, as this was
the first report of this disorder in association with VCFS. In the
patient reported by Budarf et al. (1995), Ludlow et al. (1996)
identified a mutation in the upstream promoter of the GP1BB gene
(138720.0004). Thus, in this patient, BSS resulted from deletion of 1
copy of the gene and mutation in the other copy.
Kunishima et al. (1997) described missense mutations in the GP1BB gene
(138720.0001, 138720.0002) that impaired the GP Ib alpha/beta disulfide
linkage in a family with giant platelets.
Moran et al. (2000) identified a trp21-to-ter mutation (138720.0003) in
the GP1BB gene resulting in Bernard-Soulier syndrome. Studies of
transient coexpression of this mutant, together with wildtype GP1BA and
GP9, demonstrated a failure of GP9 expression on the surface of the
testing cells. Other studies indicated that GP1BB affected the surface
expression of the complex of the GP Ib-IX complex by failing to support
the insertion of GP Ib-alpha and GP IX into the platelet membrane.
ANIMAL MODEL
Kato et al. (2004) found that Gp1bb-null mice had macrothrombocytopenia
and a severe bleeding phenotype. Electron microscropy showed increased
size of the alpha-granules compared to control alpha-granules. Western
blot analysis showed overexpression of Sept5, a gene that resides
approximately 250 nucleotides 5-prime to the Gp1bb gene and has been
associated with modulating exocytosis from neurons and platelets as part
of a presynaptic protein complex. Increased Sept5 protein levels were
seen specifically in megakaryocytes and not in brain lysates of
Gp1bb-null mice. The authors suggested that deletion of a large portion
of the Gp1bb transcript in order to create the mouse model affected
expression of the neighboring Sept5 gene. The findings unexpectedly
implicated the SEPT5 gene in the maintenance of normal alpha-granule
size, perhaps by mediating vesicle fusion.
*FIELD* AV
.0001
MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE
GP1BB, TYR88CYS
Kunishima et al. (1997) reported 2 Japanese sisters with a giant
platelet disorder that was not accompanied by thrombocytopenia or
leukocyte inclusions. During childhood, they experienced frequent
episodes of epistaxis, but thereafter the tendency to bleed settled.
Platelets from the index patient did not aggregate with ristocetin, and
she had a prolonged bleeding time (9.5 minutes, normal range 2-5
minutes). Immunoblot analysis under nonreduced conditions showed that
most of the GP Ib-alpha in the patient's platelets was not disulfide
linked with GP Ib-beta. DNA sequencing showed compound heterozygosity
for 2 independent missense mutations in the GP1BB gene: from tyr (TAC)
to cys (TGC) at residue 88, and from ala (GCC) to pro (CCC) at residue
108 (138720.0002). These mutations were thought to result in decreased
expression of the GP Ib/IX complex and to influence the association of
the complex with the membrane skeleton, consequently impairing normal
platelet morphology. The authors suggested that the phenotype caused by
mutations in the subunits of the GP Ib/IX complex could span the
spectrum from a normal phenotype, to isolated giant platelet disorder,
to a full-blown bleeding disorder such as Bernard-Soulier syndrome
(231200).
.0002
MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE
GP1BB, ALA108PRO
See 138720.0001 and Kunishima et al. (1997).
.0003
BERNARD SOULIER SYNDROME, TYPE B
GP1BB, TRP21TER
In a patient with Bernard-Soulier syndrome (231200), Moran et al. (2000)
found a G-to-A transition at nucleotide 159 of the GP1BB gene, resulting
in a premature termination of translation at amino acid trp21. The
patient was a 57-year-old Irish man with a severe bleeding diathesis.
The diagnosis of BSS was based on the presence of thrombocytopenia,
large platelets on peripheral blood smear, and a profuse bleeding
tendency requiring transfusion. Bleeding occurred both spontaneously and
after minor surgical procedures. The spontaneous bleeding apparently
stopped when the patient was about 20 years of age, but the
thrombocytopenia persisted. The patient's bleeding time was longer than
15 minutes. The patient's parents were first cousins and had no history
of abnormal bleeding. The mutation was present in homozygous form. Moran
et al. (2000) stated that this was the first report of homozygosity for
a mutation in the GP1BB gene.
.0004
BERNARD SOULIER SYNDROME, TYPE B
GP1BB, C-G, -133
In patient reported by Budarf et al. (1995) with Bernard-Soulier
syndrome (231200), velocardiofacial syndrome (192430), and a deletion in
chromosome 22q, Ludlow et al. (1996) identified a C-G transition at
position -133 in the 5-prime upstream region of the GP1BB gene,
resulting in disruption of a GATA consensus binding sequence and a
decrease in promoter activity. Thus, in this patient, BSS resulted from
deletion of 1 copy of the gene and mutation in the other copy.
*FIELD* RF
1. Budarf, M. L.; Konkle, B. A.; Ludlow, L. B.; Michaud, D.; Li, M.;
Yamashiro, D. J.; McDonald-McGinn, D.; Zackai, E. H.; Driscoll, D.
A.: Identification of a patient with Bernard-Soulier syndrome and
a deletion in the DiGeorge/velo-cardio-facial chromosomal region in
22q11.2. Hum. Molec. Genet. 4: 763-766, 1995.
2. Kato, K.; Martinez, C.; Russell, S.; Nurden, P.; Nurden, A.; Fiering,
S.; Ware, J.: Genetic deletion of mouse platelet glycoprotein Ib-beta
produces a Bernard-Soulier phenotype with increased alpha-granule
size. Blood 104: 2339-2344, 2004.
3. Kelly, M. D.; Essex, D. W.; Shapiro, S. S.; Meloni, F. J.; Druck,
T.; Huebner, K.; Konkle, B. A.: Complementary DNA cloning of the
alternatively expressed endothelial cell glycoprotein Ib-beta (GPIb-beta)
and localization of the GPIb-beta gene to chromosome 22. J. Clin.
Invest. 93: 2417-2424, 1994.
4. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya, T.;
Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
5. Lopez, J. A.; Andrews, R. K.; Afshar-Kharghan, V.; Berndt, M. C.
: Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998.
6. Lopez, J. A.; Chung, D. W.; Fujikawa, K.; Hagen, F. S.; Davie,
E. W.; Roth, G. J.: The alpha and beta chains of human platelet glycoprotein
Ib are both transmembrane proteins containing a leucine-rich amino
acid sequence. Proc. Nat. Acad. Sci. 85: 2135-2139, 1988.
7. Ludlow, L. B.; Schick, B. P.; Budarf, M. L.; Driscoll, D. A.; Zackai,
E. H.; Cohen, A.; Konkle, B. A.: Identification of a mutation in
a GATA binding site of the platelet glycoprotein Ib-beta promoter
resulting in the Bernard-Soulier syndrome. J. Biol. Chem. 271: 22076-22080,
1996.
8. Moran, N.; Morateck, P. A.; Deering, A.; Ryan, M.; Montgomery,
R. R.; Fitzgerald, D. J.; Kenny, D.: Surface expression of glycoprotein
Ib-alpha is dependent on glycoprotein Ib-beta: evidence from a novel
mutation causing Bernard-Soulier syndrome. Blood 96: 532-539, 2000.
9. Roth, G. J.: The wanderings of a platelet gene: what is 'neo'
Ib-beta telling us? (Editorial) J. Clin. Invest. 93: 2301-2302,
1994.
10. Yagi, M.; Edelhoff, S.; Disteche, C. M.; Roth, G. J.: Structural
characterization and chromosomal location of the gene encoding human
platelet glycoprotein Ib-beta. J. Biol. Chem. 269: 17424-17427,
1994.
11. Zieger, B.; Hashimoto, Y.; Ware, J.: Alternative expression of
platelet glycoprotein Ib-beta mRNA from an adjacent 5-prime gene with
an imperfect polyadenylation signal sequence. J. Clin. Invest. 99:
520-525, 1997.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/19/2009
Cassandra L. Kniffin - reorganized: 6/24/2003
Cassandra L. Kniffin - updated: 6/20/2003
Victor A. McKusick - updated: 9/28/2000
Victor A. McKusick - updated: 12/15/1999
Victor A. McKusick - updated: 12/6/1999
Victor A. McKusick - updated: 3/16/1997
*FIELD* CD
Victor A. McKusick: 1/4/1991
*FIELD* ED
carol: 10/04/2010
ckniffin: 8/31/2010
wwang: 12/10/2009
ckniffin: 11/19/2009
terry: 7/24/2003
carol: 6/24/2003
ckniffin: 6/24/2003
ckniffin: 6/20/2003
terry: 9/28/2000
alopez: 12/21/1999
terry: 12/15/1999
mgross: 12/8/1999
terry: 12/6/1999
carol: 7/13/1998
alopez: 6/16/1998
terry: 7/7/1997
mark: 3/17/1997
mark: 3/16/1997
terry: 3/10/1997
mark: 6/8/1995
jason: 7/12/1994
carol: 7/22/1993
supermim: 3/16/1992
carol: 1/8/1991
carol: 1/4/1991
MIM
231200
*RECORD*
*FIELD* NO
231200
*FIELD* TI
#231200 BERNARD-SOULIER SYNDROME; BSS
;;BLEEDING DISORDER, PLATELET-TYPE, 1; BDPLT1;;
read morePLATELET GLYCOPROTEIN Ib DEFICIENCY;;
GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF;;
VON WILLEBRAND FACTOR RECEPTOR DEFICIENCY
BERNARD-SOULIER SYNDROME, TYPE A1, INCLUDED;;
BERNARD-SOULIER SYNDROME, TYPE B, INCLUDED;;
BERNARD-SOULIER SYNDROME, TYPE C, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Bernard-Soulier
syndrome (BSS) has been found to be caused by mutation in the GP1BA gene
(606672), the GP1BB gene (138720), or the GP9 gene (173515); the forms
of BSS caused by homozygous or compound heterozygous mutation in these
genes are here referred to as types A1, B, and C, respectively.
See also autosomal dominant Bernard-Soulier syndrome (BSSA2; 153670),
which can be caused by heterozygous mutation in the GP1BA gene. It is
much less common than autosomal recessive Bernard-Soulier syndrome.
DESCRIPTION
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder
caused by a defect in or deficiency of the platelet membrane von
Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP
Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA,
GP1BB, GP9, and GP5 (173511).
- Genetic Heterogeneity of Platelet-Type Bleeding Disorders
Inherited platelet disorders are a heterogeneous group of bleeding
disorders affecting platelet number, function, or both. Functional
defects can involve platelet receptors, signaling pathways, cytoskeletal
proteins, granule contents, activation, or aggregation (review by Cox et
al., 2011 and Nurden and Nurden, 2011).
Platelet-type bleeding disorders include Bernard-Soulier syndrome
(BDPLT1); Glanzmann thrombasthenia (BDPLT2; 273800), caused by mutation
in the ITGA2B (607759) or ITGB3 (173470) gene; pseudo-von Willebrand
disease (BDPLT3; 177820), caused by mutation in the GP1BA gene (606672);
gray platelet syndrome (BDPLT4; 139090), caused by mutation in the
NBEAL2 gene (614169); Quebec platelet disorder (BDPLT5; 601709), caused
by tandem duplication of the PLAU gene (191840); May-Hegglin anomaly
(BDPLT6; 155100), caused by mutation in the MYH9 gene (160775); Scott
syndrome (BDPLT7; 262890), caused by mutation in the TMEM16F gene
(608663); BDPLT8 (609821), caused by mutation in the P2RY12 gene
(600515); BDPLT9 (614200), associated with deficiency of the
glycoprotein Ia/IIa receptor (see ITGA2; 192974); glycoprotein IV
deficiency (BDPLT10; 608404), caused by mutation in the CD36 gene
(173510); BDPLT11 (614201), caused by mutation in the GP6 gene (605546);
BDPLT12 (605735), associated with a deficiency of platelet COX1
(176805); susceptibility to BDPLT13 (614009), caused by mutation in the
TBXA2R gene (188070); BDPLT14 (614158), associated with deficiency of
thromboxane synthetase (TBXAS1; 274180); BDPLT15 (615193), caused by
mutation in the ACTN1 gene (102575); BDPLT16 (187800), caused by
mutation in the ITGA2B (607759) or ITGB3 (173470) gene; and BDPLT17
(187900), caused by mutation in the GFI1B gene (604383).
See reviews by Rao (2003), Cox et al. (2011), and Nurden and Nurden
(2011).
For a discussion of the genetic heterogeneity of hereditary
thrombocytopenia, see THC1 (313900).
CLINICAL FEATURES
Bernard-Soulier syndrome and other platelet disorders have some similar
clinical features, including mucosal bleeding, purpuric skin bleeding,
epistaxis, and menorrhagia. In BSS, bleeding time is prolonged (in some
cases longer than 20 minutes), platelets are large, and there is no
platelet aggregation in response to ristocetin or addition of von
Willebrand factor. Thrombocytopenia may or may not be present (Lopez et
al., 1998).
Bernard and Soulier (1948) described a congenital bleeding disorder in
patients who had unusually large platelets and a moderate degree of
thrombocytopenia. All had a markedly prolonged bleeding time. The same
abnormality was described in a family by Kanska et al. (1963). Cullum et
al. (1967) described 2 brothers from a consanguineous family of Sicilian
origin with a bleeding disorder characterized by thrombocytopenia,
abnormally large platelets, prolonged bleeding time, low platelet
thromboplastic activity, and normal clotting retraction. All 5 of the
brothers' children had abnormal platelet morphology. Multiple other
members of the extended family had abnormal platelets without the full
bleeding disorder. The authors concluded that the 2 affected brothers
were homozygous and the other members with isolated abnormal platelet
morphology were heterozygotes. The phospholipid content of platelets was
increased. Cullum et al. (1967) suggested that abnormally rapid removal
of the bizarre platelets may be responsible for thrombocytopenia. Weiss
et al. (1974) studied 2 black first cousins with the disorder.
CLINICAL MANAGEMENT
In the case of a Swedish patient with Bernard-Soulier syndrome,
Waldenstrom et al. (1991) found that the parents had common ancestors in
the 17th century. In this and another patient, bleeding time was
shortened by infusion of dDAVP (1-deamino-8D-arginine vasopressin),
although it was not completely normalized.
PATHOGENESIS
Grottum and Solum (1969) found reduced electrophoretic mobility of BSS
platelets due to a marked decrease in the concentration of sialic acid
on their membranes.
Weiss et al. (1974) noted that the adhesion of BSS platelets to rabbit
aortic subendothelium was impaired. The authors suggested that there may
be a reduced or abnormal glycoprotein involved, and they presented
evidence suggesting that platelets in this syndrome lack a receptor for
the von Willebrand factor.
In 2 patients with the Bernard-Soulier syndrome, Nurden and Caen (1975)
were unable to find more than traces of a 155,000 molecular mass
glycoprotein in membrane fraction from platelets. Previously reported
findings of sialic acid content and reduced electrophoretic mobility of
Bernard-Soulier platelets were consistent. Caen et al. (1976) confirmed
a defect in BSS platelet adhesion to rabbit aorta subendothelium. The
factor VIII-von Willebrand protein was apparently normal on
Bernard-Soulier platelets when studied by an immuno-electron-microscopic
technique; however, a reduced content of a major platelet glycoprotein
was found by two methods.
In 3 patients with the Bernard-Soulier syndrome, Kunicki et al. (1978)
could not detect the platelet membrane receptor for quinidine and
quinine-dependent antibodies. The platelets were likewise deficient in
glycoproteins Ib and Is. In normal platelets, apparently, complete
cleavage of the glycoproteins had little effect on antibody receptor
activity, suggesting the presence of a second membrane defect in BSS.
Hagen et al. (1980) stated that there was clear evidence that there is a
defect in von Willebrand receptor in the Bernard-Soulier syndrome (see
also Moake et al., 1980), and that the normal receptor is glycoprotein I
(Nurden and Caen, 1975). Heterozygotes (e.g., parents) have a decrease
in glycoprotein I but no impairment of platelet function and no abnormal
bleeding.
Montgomery et al. (1983) demonstrated that an assay using monoclonal
antibodies raised in the mouse can recognize the deficiency of
glycoprotein Ib in the Bernard-Soulier syndrome and of the glycoprotein
IIb/IIIa in Glanzmann thrombasthenia (GTA; 273800).
Stricker et al. (1985) described acquired Bernard-Soulier syndrome in a
patient with a lymphoproliferative disorder. They demonstrated an IgG
antibody that inhibited aggregation of normal platelets by ristocetin
and by von Willebrand factor. By Western blotting, they found that the
antibody bound specifically to an antigen of MW 210,000 present in
normal platelets but missing in BSS platelets.
MOLECULAR GENETICS
In a patient with autosomal recessive Bernard-Soulier syndrome, Ware et
al. (1990) identified a homozygous nonsense mutation in the GP1BA gene
(606672.0001), which encodes the alpha chain of the GP Ib receptor.
By RFLP analysis, Finch et al. (1990) ruled out the GP1BA gene as the
site of the mutation in a BSS family with 2 affected sibs. The authors
suggested that the cause of BSS in this family was due to other genes
encoding platelet membrane glycoproteins, including GP1BB, GP IX, and
possibly GP V, which may result in failure of assembly and cell surface
expression of the von Willebrand factor receptor complex. This
suggestion came from the observation that other membrane complexes such
as platelet GP IIb-IIIa (273800, 173470) and the T-cell receptor/CD3
complex (186790, 186830, 186740) require coordinate expression of
multiple subunits for normal receptor assembly.
In a male patient with the velocardiofacial syndrome caused by a
deletion in chromosome 22q and symptoms of BSS, Ludlow et al. (1996)
identified a mutation in the upstream promoter of the GP1BB gene
(138720.0003). Thus, in this patient, BSS resulted from deletion of 1
copy of the gene and mutation in the other copy.
In a family with BSS, Wright et al. (1993) identified compound
heterozygous mutations in the GP9 gene (173515.0001, 173515.0002). The
authors suggested that abnormal GP IX prevented stable assembly of the
GP Ib complex.
Noda et al. (1995) reported 2 BSS patients: one had a mutation in the
GP9 gene and the other had a mutation in the GP1BA gene. They noted that
abnormality of a single component of the receptor complex resulted in
heterogeneous surface expression of all the components.
In 2 Japanese sisters with giant platelets, mild childhood bleeding, and
impaired ristocetin aggregation, Kunishima et al. (1997) identified
compound heterozygosity for mutations in the GP1BB gene
(138720.0001-138720.0002). The authors suggested that the phenotype
caused by mutations in the subunits of the GP Ib complex could span the
spectrum from a normal phenotype, to isolated giant platelet disorder,
to full-blown Bernard-Soulier syndrome.
ANIMAL MODEL
Ware et al. (2000) disrupted the Gp1ba gene of the mouse and described a
murine model recapitulating the hallmark characteristics of human
Bernard-Soulier syndrome. Using transgenic technology, they rescued the
murine BSS phenotype by expression of the human glycoprotein Ib-alpha
subunit on the surface of circulating mouse platelets.
Kato et al. (2004) found that Gp1bb-null mice had macrothrombocytopenia
and a severe bleeding phenotype. Electron microscopy showed increased
size of the alpha-granules compared to control alpha-granules, possibly
resulting from disruption of the neighboring Sept5 gene (602724),
approximately 250 nucleotides 5-prime to the Gp1bb gene. Sept5 protein
levels in platelets from Gp1bb-null mice were 2- to 3-fold increased
compared to controls.
*FIELD* SA
Howard et al. (1973); Maldonado et al. (1975); Miller et al. (1991)
*FIELD* RF
1. Bernard, J.; Soulier, J.-P.: Sur une nouvelle variete de dystrophie
thrombocytaire-hemoragipare congenitale. Sem. Hop. Paris 24: 3217-3223,
1948.
2. Caen, J. P.; Nurden, A. T.; Jeanneau, C.; Michel, H.; Tobelem,
G.; Levy-Toledano, S.; Sultan, Y.; Valensi, F.; Bernard, J.: Bernard-Soulier
syndrome: a new platelet glycoprotein abnormality. Its relationship
with platelet adhesion to subendothelium and with the factor VIII
von Willebrand protein. J. Lab. Clin. Med. 87: 587-596, 1976.
3. Cox, K.; Price, V.; Kahr, W. H. A.: Inherited platelet disorders:
a clinical approach to diagnosis and management. Expert Rev. Hematol. 4:
455-472, 2011.
4. Cullum, C.; Cooney, D. P.; Schrier, S. L.: Familial thrombocytopenic
thrombocytopathy. Brit. J. Haemat. 13: 147-159, 1967.
5. Finch, C. N.; Miller, J. L.; Lyle, V. A.; Handin, R. I.: Evidence
that an abnormality in the glycoprotein Ib alpha gene is not the cause
of abnormal platelet function in a family with classic Bernard-Soulier
disease. Blood 75: 2357-2362, 1990.
6. Grottum, K. A.; Solum, N. O.: Congenital thrombocytopenia with
giant platelets: a defect in the platelet membrane. Brit. J. Haemat. 16:
277-290, 1969.
7. Hagen, I.; Nurden, A.; Bjerrum, O. J.; Solum, N. O.; Caen, J.:
Immunochemical evidence for protein abnormalities in platelets from
patients with Glanzmann's thrombasthenia and Bernard-Soulier syndrome. J.
Clin. Invest. 65: 722-731, 1980.
8. Howard, M. A.; Hutton, R. A.; Hardisty, R. M.: Hereditary giant
platelet syndrome: a disorder of a new aspect of platelet function. Brit.
Med. J. 4: 586-589, 1973.
9. Kanska, B.; Niewiarowski, S.; Ostrowski, L.: Macrothrombocytic
thrombopathia. Clinical, coagulation and hereditary aspects. Thromb.
Diath. Haemorrh. 10: 88-100, 1963.
10. Kato, K.; Martinez, C.; Russell, S.; Nurden, P.; Nurden, A.; Fiering,
S.; Ware, J.: Genetic deletion of mouse platelet glycoprotein Ib-beta
produces a Bernard-Soulier phenotype with increased alpha-granule
size. Blood 104: 2339-2344, 2004.
11. Kunicki, T. J.; Johnson, M. M.; Aster, R. H.: Absence of the
platelet receptor for drug-dependent antibodies in the Bernard-Soulier
syndrome. J. Clin. Invest. 62: 716-719, 1978.
12. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya,
T.; Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
13. Lopez, J. A.; Andrews, R. K.; Afshar-Kharghan, V.; Berndt, M.
C.: Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998.
14. Ludlow, L. B.; Schick, B. P.; Budarf, M. L.; Driscoll, D. A.;
Zackai, E. H.; Cohen, A.; Konkle, B. A.: Identification of a mutation
in a GATA binding site of the platelet glycoprotein Ib-beta promoter
resulting in the Bernard-Soulier syndrome. J. Biol. Chem. 271: 22076-22080,
1996.
15. Maldonado, J. E.; Gilchrist, G. S.; Brigden, L. P.; Bowie, E.
J.: Ultrastructure of platelets in Bernard-Soulier syndrome. Mayo
Clin. Proc. 50: 402-406, 1975.
16. Miller, J. L.; Cunningham, D.; Lyle, V. A.; Finch, C. N.: Mutation
in the gene encoding the alpha chain of platelet glycoprotein Ib in
platelet-type von Willebrand disease. Proc. Nat. Acad. Sci. 88:
4761-4765, 1991.
17. Moake, J. L.; Olson, J. D.; Troll, J. H.; Tang, S. S.; Funicella,
T.; Peterson, D. M.: Binding of radioiodinated human von Willebrand
factor to Bernard-Soulier, thrombasthenic and von Willebrand's disease
platelets. Thromb. Res. 19: 21-27, 1980.
18. Montgomery, R. R.; Kunicki, T. J.; Taves, C.; Pidard, D.; Corcoran,
M.: Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia
with a monoclonal assay on whole blood. J. Clin. Invest. 71: 385-389,
1983.
19. Noda, M.; Fujimura, K.; Takafuta, T.; Shimomura, T.; Fujimoto,
T.; Yamamoto, N.; Tanoue, K.; Arai, M.; Suehiro, A.; Kakishita, E.;
Shimsaki, A.; Kuramoto, A.: Heterogeneous expression of glycoprotein
Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome
caused by different genetic abnormalities. Thromb. Haemost. 74:
1411-1415, 1995. Note: Erratum: Thromb. Haemost. 75: 700 only, 1996.
20. Nurden, A.; Nurden, P.: Advances in our understanding of the
molecular basis of disorders of platelet function. J. Thromb. Haemost. 9
(suppl. 1): 76-91, 2011.
21. Nurden, A. T.; Caen, J. P.: Specific roles for platelet surface
glycoproteins in platelet function. Nature 255: 720-722, 1975.
22. Rao, A. K.: Inherited defects in platelet signaling mechanisms. J.
Thromb. Haemost. 1: 671-681, 2003.
23. Stricker, R. B.; Wong, D.; Saks, S. R.; Corash, L.; Shuman, M.
A.: Acquired Bernard-Soulier syndrome: evidence for the role of a
210,000-molecular weight protein in the interaction of platelets with
von Willebrand factor. J. Clin. Invest. 76: 1274-1278, 1985.
24. Waldenstrom, E.; Holmberg, L.; Axelsson, U.; Winqvist, I.; Nilsson,
I. M.: Bernard-Soulier syndrome in two Swedish families: effect of
dDAVP on bleeding time. Europ. J. Haemat. 46: 182-187, 1991.
25. Ware, J.; Russell, S.; Ruggeri, Z. M.: Generation and rescue
of a murine model of platelet dysfunction: the Bernard-Soulier syndrome. Proc.
Nat. Acad. Sci. 97: 2803-2808, 2000.
26. Ware, J.; Russell, S. R.; Vicente, V.; Scharf, R. E.; Tomer, A.;
McMillan, R.; Ruggeri, Z. M.: Nonsense mutation in the glycoprotein
Ib-alpha coding sequence associated with Bernard-Soulier syndrome. Proc.
Nat. Acad. Sci. 87: 2026-2030, 1990.
27. Weiss, H. J.; Tschopp, T. B.; Baumgartner, H. R.; Sussman, I.
I.; Johnson, M. M.; Egan, J. J.: Decreased adhesion of giant (Bernard-Soulier)
platelets to subendothelium: further implications on the role of the
von Willebrand factor in hemostasis. Am. J. Med. 57: 920-925, 1974.
28. Wright, S. D.; Michaelides, K.; Johnson, D. J. D.; West, N. C.;
Tuddenham, E. G. D.: Double heterozygosity for mutations in the platelet
glycoprotein IX gene in three siblings with Bernard-Soulier syndrome. Blood 81:
2339-2347, 1993.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Nose];
Epistaxis
ABDOMEN:
[Gastrointestinal];
Hemorrhage
GENITOURINARY:
[Internal genitalia, female];
Menorrhagia
SKIN, NAILS, HAIR:
[Skin];
Purpura
HEMATOLOGY:
Congenital bleeding diathesis;
Large platelets;
Mild thrombocytopenia
LABORATORY ABNORMALITIES:
Prolonged bleeding time;
Reduced platelet glycoprotein Ib complex;
Normal platelet aggregation with ADP, collagen, epinephrine;
Absent platelet agglutination in presence of ristocetin
MOLECULAR BASIS:
Caused by mutation in the platelet glycoprotein Ib, alpha polypeptide,
gene (GP1BA, 606672.0001);
Caused by mutation in the platelet glycoprotein Ib, beta polypeptide,
gene (GP1BB, 138720.0001);
Caused by mutation in the platelet glycoprotein IX gene (GP9, 173515.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 5/18/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/24/2011
ckniffin: 11/19/2009
joanna: 8/23/2001
kayiaros: 5/18/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 9/8/2011
Cassandra L. Kniffin - updated: 11/19/2009
Cassandra L. Kniffin - reorganized: 6/24/2003
Cassandra L. Kniffin - updated: 6/20/2003
Victor A. McKusick - updated: 1/24/2002
Victor A. McKusick - updated: 4/5/2001
Victor A. McKusick - updated: 4/18/2000
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 9/19/1997
Stylianos E. Antonarakis - updated: 7/5/1996
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 01/28/2014
ckniffin: 1/27/2014
carol: 5/3/2013
ckniffin: 4/25/2013
carol: 4/24/2013
ckniffin: 4/23/2013
terry: 3/28/2013
alopez: 10/22/2012
carol: 9/14/2011
ckniffin: 9/8/2011
carol: 7/27/2011
carol: 10/4/2010
wwang: 12/10/2009
ckniffin: 11/19/2009
ckniffin: 11/12/2009
terry: 7/24/2003
carol: 6/24/2003
ckniffin: 6/20/2003
ckniffin: 6/19/2003
carol: 5/15/2003
terry: 1/24/2002
mcapotos: 10/2/2001
mcapotos: 9/24/2001
terry: 9/20/2001
cwells: 5/3/2001
mcapotos: 4/11/2001
mcapotos: 4/6/2001
terry: 4/5/2001
mcapotos: 5/10/2000
terry: 4/18/2000
carol: 1/5/1999
dholmes: 7/22/1998
carol: 7/16/1998
terry: 7/13/1998
terry: 3/24/1998
mark: 9/23/1997
terry: 9/19/1997
alopez: 6/11/1997
alopez: 3/19/1997
mark: 3/17/1997
mark: 12/26/1996
mark: 8/27/1996
terry: 7/24/1996
carol: 7/5/1996
terry: 7/3/1996
terry: 6/26/1995
mark: 6/7/1995
carol: 3/28/1994
mimadm: 2/19/1994
carol: 9/8/1993
carol: 6/4/1993
*RECORD*
*FIELD* NO
231200
*FIELD* TI
#231200 BERNARD-SOULIER SYNDROME; BSS
;;BLEEDING DISORDER, PLATELET-TYPE, 1; BDPLT1;;
read morePLATELET GLYCOPROTEIN Ib DEFICIENCY;;
GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF;;
VON WILLEBRAND FACTOR RECEPTOR DEFICIENCY
BERNARD-SOULIER SYNDROME, TYPE A1, INCLUDED;;
BERNARD-SOULIER SYNDROME, TYPE B, INCLUDED;;
BERNARD-SOULIER SYNDROME, TYPE C, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Bernard-Soulier
syndrome (BSS) has been found to be caused by mutation in the GP1BA gene
(606672), the GP1BB gene (138720), or the GP9 gene (173515); the forms
of BSS caused by homozygous or compound heterozygous mutation in these
genes are here referred to as types A1, B, and C, respectively.
See also autosomal dominant Bernard-Soulier syndrome (BSSA2; 153670),
which can be caused by heterozygous mutation in the GP1BA gene. It is
much less common than autosomal recessive Bernard-Soulier syndrome.
DESCRIPTION
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder
caused by a defect in or deficiency of the platelet membrane von
Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP
Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA,
GP1BB, GP9, and GP5 (173511).
- Genetic Heterogeneity of Platelet-Type Bleeding Disorders
Inherited platelet disorders are a heterogeneous group of bleeding
disorders affecting platelet number, function, or both. Functional
defects can involve platelet receptors, signaling pathways, cytoskeletal
proteins, granule contents, activation, or aggregation (review by Cox et
al., 2011 and Nurden and Nurden, 2011).
Platelet-type bleeding disorders include Bernard-Soulier syndrome
(BDPLT1); Glanzmann thrombasthenia (BDPLT2; 273800), caused by mutation
in the ITGA2B (607759) or ITGB3 (173470) gene; pseudo-von Willebrand
disease (BDPLT3; 177820), caused by mutation in the GP1BA gene (606672);
gray platelet syndrome (BDPLT4; 139090), caused by mutation in the
NBEAL2 gene (614169); Quebec platelet disorder (BDPLT5; 601709), caused
by tandem duplication of the PLAU gene (191840); May-Hegglin anomaly
(BDPLT6; 155100), caused by mutation in the MYH9 gene (160775); Scott
syndrome (BDPLT7; 262890), caused by mutation in the TMEM16F gene
(608663); BDPLT8 (609821), caused by mutation in the P2RY12 gene
(600515); BDPLT9 (614200), associated with deficiency of the
glycoprotein Ia/IIa receptor (see ITGA2; 192974); glycoprotein IV
deficiency (BDPLT10; 608404), caused by mutation in the CD36 gene
(173510); BDPLT11 (614201), caused by mutation in the GP6 gene (605546);
BDPLT12 (605735), associated with a deficiency of platelet COX1
(176805); susceptibility to BDPLT13 (614009), caused by mutation in the
TBXA2R gene (188070); BDPLT14 (614158), associated with deficiency of
thromboxane synthetase (TBXAS1; 274180); BDPLT15 (615193), caused by
mutation in the ACTN1 gene (102575); BDPLT16 (187800), caused by
mutation in the ITGA2B (607759) or ITGB3 (173470) gene; and BDPLT17
(187900), caused by mutation in the GFI1B gene (604383).
See reviews by Rao (2003), Cox et al. (2011), and Nurden and Nurden
(2011).
For a discussion of the genetic heterogeneity of hereditary
thrombocytopenia, see THC1 (313900).
CLINICAL FEATURES
Bernard-Soulier syndrome and other platelet disorders have some similar
clinical features, including mucosal bleeding, purpuric skin bleeding,
epistaxis, and menorrhagia. In BSS, bleeding time is prolonged (in some
cases longer than 20 minutes), platelets are large, and there is no
platelet aggregation in response to ristocetin or addition of von
Willebrand factor. Thrombocytopenia may or may not be present (Lopez et
al., 1998).
Bernard and Soulier (1948) described a congenital bleeding disorder in
patients who had unusually large platelets and a moderate degree of
thrombocytopenia. All had a markedly prolonged bleeding time. The same
abnormality was described in a family by Kanska et al. (1963). Cullum et
al. (1967) described 2 brothers from a consanguineous family of Sicilian
origin with a bleeding disorder characterized by thrombocytopenia,
abnormally large platelets, prolonged bleeding time, low platelet
thromboplastic activity, and normal clotting retraction. All 5 of the
brothers' children had abnormal platelet morphology. Multiple other
members of the extended family had abnormal platelets without the full
bleeding disorder. The authors concluded that the 2 affected brothers
were homozygous and the other members with isolated abnormal platelet
morphology were heterozygotes. The phospholipid content of platelets was
increased. Cullum et al. (1967) suggested that abnormally rapid removal
of the bizarre platelets may be responsible for thrombocytopenia. Weiss
et al. (1974) studied 2 black first cousins with the disorder.
CLINICAL MANAGEMENT
In the case of a Swedish patient with Bernard-Soulier syndrome,
Waldenstrom et al. (1991) found that the parents had common ancestors in
the 17th century. In this and another patient, bleeding time was
shortened by infusion of dDAVP (1-deamino-8D-arginine vasopressin),
although it was not completely normalized.
PATHOGENESIS
Grottum and Solum (1969) found reduced electrophoretic mobility of BSS
platelets due to a marked decrease in the concentration of sialic acid
on their membranes.
Weiss et al. (1974) noted that the adhesion of BSS platelets to rabbit
aortic subendothelium was impaired. The authors suggested that there may
be a reduced or abnormal glycoprotein involved, and they presented
evidence suggesting that platelets in this syndrome lack a receptor for
the von Willebrand factor.
In 2 patients with the Bernard-Soulier syndrome, Nurden and Caen (1975)
were unable to find more than traces of a 155,000 molecular mass
glycoprotein in membrane fraction from platelets. Previously reported
findings of sialic acid content and reduced electrophoretic mobility of
Bernard-Soulier platelets were consistent. Caen et al. (1976) confirmed
a defect in BSS platelet adhesion to rabbit aorta subendothelium. The
factor VIII-von Willebrand protein was apparently normal on
Bernard-Soulier platelets when studied by an immuno-electron-microscopic
technique; however, a reduced content of a major platelet glycoprotein
was found by two methods.
In 3 patients with the Bernard-Soulier syndrome, Kunicki et al. (1978)
could not detect the platelet membrane receptor for quinidine and
quinine-dependent antibodies. The platelets were likewise deficient in
glycoproteins Ib and Is. In normal platelets, apparently, complete
cleavage of the glycoproteins had little effect on antibody receptor
activity, suggesting the presence of a second membrane defect in BSS.
Hagen et al. (1980) stated that there was clear evidence that there is a
defect in von Willebrand receptor in the Bernard-Soulier syndrome (see
also Moake et al., 1980), and that the normal receptor is glycoprotein I
(Nurden and Caen, 1975). Heterozygotes (e.g., parents) have a decrease
in glycoprotein I but no impairment of platelet function and no abnormal
bleeding.
Montgomery et al. (1983) demonstrated that an assay using monoclonal
antibodies raised in the mouse can recognize the deficiency of
glycoprotein Ib in the Bernard-Soulier syndrome and of the glycoprotein
IIb/IIIa in Glanzmann thrombasthenia (GTA; 273800).
Stricker et al. (1985) described acquired Bernard-Soulier syndrome in a
patient with a lymphoproliferative disorder. They demonstrated an IgG
antibody that inhibited aggregation of normal platelets by ristocetin
and by von Willebrand factor. By Western blotting, they found that the
antibody bound specifically to an antigen of MW 210,000 present in
normal platelets but missing in BSS platelets.
MOLECULAR GENETICS
In a patient with autosomal recessive Bernard-Soulier syndrome, Ware et
al. (1990) identified a homozygous nonsense mutation in the GP1BA gene
(606672.0001), which encodes the alpha chain of the GP Ib receptor.
By RFLP analysis, Finch et al. (1990) ruled out the GP1BA gene as the
site of the mutation in a BSS family with 2 affected sibs. The authors
suggested that the cause of BSS in this family was due to other genes
encoding platelet membrane glycoproteins, including GP1BB, GP IX, and
possibly GP V, which may result in failure of assembly and cell surface
expression of the von Willebrand factor receptor complex. This
suggestion came from the observation that other membrane complexes such
as platelet GP IIb-IIIa (273800, 173470) and the T-cell receptor/CD3
complex (186790, 186830, 186740) require coordinate expression of
multiple subunits for normal receptor assembly.
In a male patient with the velocardiofacial syndrome caused by a
deletion in chromosome 22q and symptoms of BSS, Ludlow et al. (1996)
identified a mutation in the upstream promoter of the GP1BB gene
(138720.0003). Thus, in this patient, BSS resulted from deletion of 1
copy of the gene and mutation in the other copy.
In a family with BSS, Wright et al. (1993) identified compound
heterozygous mutations in the GP9 gene (173515.0001, 173515.0002). The
authors suggested that abnormal GP IX prevented stable assembly of the
GP Ib complex.
Noda et al. (1995) reported 2 BSS patients: one had a mutation in the
GP9 gene and the other had a mutation in the GP1BA gene. They noted that
abnormality of a single component of the receptor complex resulted in
heterogeneous surface expression of all the components.
In 2 Japanese sisters with giant platelets, mild childhood bleeding, and
impaired ristocetin aggregation, Kunishima et al. (1997) identified
compound heterozygosity for mutations in the GP1BB gene
(138720.0001-138720.0002). The authors suggested that the phenotype
caused by mutations in the subunits of the GP Ib complex could span the
spectrum from a normal phenotype, to isolated giant platelet disorder,
to full-blown Bernard-Soulier syndrome.
ANIMAL MODEL
Ware et al. (2000) disrupted the Gp1ba gene of the mouse and described a
murine model recapitulating the hallmark characteristics of human
Bernard-Soulier syndrome. Using transgenic technology, they rescued the
murine BSS phenotype by expression of the human glycoprotein Ib-alpha
subunit on the surface of circulating mouse platelets.
Kato et al. (2004) found that Gp1bb-null mice had macrothrombocytopenia
and a severe bleeding phenotype. Electron microscopy showed increased
size of the alpha-granules compared to control alpha-granules, possibly
resulting from disruption of the neighboring Sept5 gene (602724),
approximately 250 nucleotides 5-prime to the Gp1bb gene. Sept5 protein
levels in platelets from Gp1bb-null mice were 2- to 3-fold increased
compared to controls.
*FIELD* SA
Howard et al. (1973); Maldonado et al. (1975); Miller et al. (1991)
*FIELD* RF
1. Bernard, J.; Soulier, J.-P.: Sur une nouvelle variete de dystrophie
thrombocytaire-hemoragipare congenitale. Sem. Hop. Paris 24: 3217-3223,
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2. Caen, J. P.; Nurden, A. T.; Jeanneau, C.; Michel, H.; Tobelem,
G.; Levy-Toledano, S.; Sultan, Y.; Valensi, F.; Bernard, J.: Bernard-Soulier
syndrome: a new platelet glycoprotein abnormality. Its relationship
with platelet adhesion to subendothelium and with the factor VIII
von Willebrand protein. J. Lab. Clin. Med. 87: 587-596, 1976.
3. Cox, K.; Price, V.; Kahr, W. H. A.: Inherited platelet disorders:
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455-472, 2011.
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thrombocytopathy. Brit. J. Haemat. 13: 147-159, 1967.
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that an abnormality in the glycoprotein Ib alpha gene is not the cause
of abnormal platelet function in a family with classic Bernard-Soulier
disease. Blood 75: 2357-2362, 1990.
6. Grottum, K. A.; Solum, N. O.: Congenital thrombocytopenia with
giant platelets: a defect in the platelet membrane. Brit. J. Haemat. 16:
277-290, 1969.
7. Hagen, I.; Nurden, A.; Bjerrum, O. J.; Solum, N. O.; Caen, J.:
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Clin. Invest. 65: 722-731, 1980.
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platelet syndrome: a disorder of a new aspect of platelet function. Brit.
Med. J. 4: 586-589, 1973.
9. Kanska, B.; Niewiarowski, S.; Ostrowski, L.: Macrothrombocytic
thrombopathia. Clinical, coagulation and hereditary aspects. Thromb.
Diath. Haemorrh. 10: 88-100, 1963.
10. Kato, K.; Martinez, C.; Russell, S.; Nurden, P.; Nurden, A.; Fiering,
S.; Ware, J.: Genetic deletion of mouse platelet glycoprotein Ib-beta
produces a Bernard-Soulier phenotype with increased alpha-granule
size. Blood 104: 2339-2344, 2004.
11. Kunicki, T. J.; Johnson, M. M.; Aster, R. H.: Absence of the
platelet receptor for drug-dependent antibodies in the Bernard-Soulier
syndrome. J. Clin. Invest. 62: 716-719, 1978.
12. Kunishima, S.; Lopez, J. A.; Kobayashi, S.; Imai, N.; Kamiya,
T.; Saito, H.; Naoe, T.: Missense mutations of the glycoprotein (GP)
Ib-beta gene impairing the GPIb alpha/beta disulfide linkage in a
family with giant platelet disorder. Blood 89: 2404-2412, 1997.
13. Lopez, J. A.; Andrews, R. K.; Afshar-Kharghan, V.; Berndt, M.
C.: Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998.
14. Ludlow, L. B.; Schick, B. P.; Budarf, M. L.; Driscoll, D. A.;
Zackai, E. H.; Cohen, A.; Konkle, B. A.: Identification of a mutation
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1996.
15. Maldonado, J. E.; Gilchrist, G. S.; Brigden, L. P.; Bowie, E.
J.: Ultrastructure of platelets in Bernard-Soulier syndrome. Mayo
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16. Miller, J. L.; Cunningham, D.; Lyle, V. A.; Finch, C. N.: Mutation
in the gene encoding the alpha chain of platelet glycoprotein Ib in
platelet-type von Willebrand disease. Proc. Nat. Acad. Sci. 88:
4761-4765, 1991.
17. Moake, J. L.; Olson, J. D.; Troll, J. H.; Tang, S. S.; Funicella,
T.; Peterson, D. M.: Binding of radioiodinated human von Willebrand
factor to Bernard-Soulier, thrombasthenic and von Willebrand's disease
platelets. Thromb. Res. 19: 21-27, 1980.
18. Montgomery, R. R.; Kunicki, T. J.; Taves, C.; Pidard, D.; Corcoran,
M.: Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia
with a monoclonal assay on whole blood. J. Clin. Invest. 71: 385-389,
1983.
19. Noda, M.; Fujimura, K.; Takafuta, T.; Shimomura, T.; Fujimoto,
T.; Yamamoto, N.; Tanoue, K.; Arai, M.; Suehiro, A.; Kakishita, E.;
Shimsaki, A.; Kuramoto, A.: Heterogeneous expression of glycoprotein
Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome
caused by different genetic abnormalities. Thromb. Haemost. 74:
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A.: Acquired Bernard-Soulier syndrome: evidence for the role of a
210,000-molecular weight protein in the interaction of platelets with
von Willebrand factor. J. Clin. Invest. 76: 1274-1278, 1985.
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*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Nose];
Epistaxis
ABDOMEN:
[Gastrointestinal];
Hemorrhage
GENITOURINARY:
[Internal genitalia, female];
Menorrhagia
SKIN, NAILS, HAIR:
[Skin];
Purpura
HEMATOLOGY:
Congenital bleeding diathesis;
Large platelets;
Mild thrombocytopenia
LABORATORY ABNORMALITIES:
Prolonged bleeding time;
Reduced platelet glycoprotein Ib complex;
Normal platelet aggregation with ADP, collagen, epinephrine;
Absent platelet agglutination in presence of ristocetin
MOLECULAR BASIS:
Caused by mutation in the platelet glycoprotein Ib, alpha polypeptide,
gene (GP1BA, 606672.0001);
Caused by mutation in the platelet glycoprotein Ib, beta polypeptide,
gene (GP1BB, 138720.0001);
Caused by mutation in the platelet glycoprotein IX gene (GP9, 173515.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 5/18/2001
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 09/24/2011
ckniffin: 11/19/2009
joanna: 8/23/2001
kayiaros: 5/18/2001
*FIELD* CN
Cassandra L. Kniffin - updated: 9/8/2011
Cassandra L. Kniffin - updated: 11/19/2009
Cassandra L. Kniffin - reorganized: 6/24/2003
Cassandra L. Kniffin - updated: 6/20/2003
Victor A. McKusick - updated: 1/24/2002
Victor A. McKusick - updated: 4/5/2001
Victor A. McKusick - updated: 4/18/2000
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 9/19/1997
Stylianos E. Antonarakis - updated: 7/5/1996
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 01/28/2014
ckniffin: 1/27/2014
carol: 5/3/2013
ckniffin: 4/25/2013
carol: 4/24/2013
ckniffin: 4/23/2013
terry: 3/28/2013
alopez: 10/22/2012
carol: 9/14/2011
ckniffin: 9/8/2011
carol: 7/27/2011
carol: 10/4/2010
wwang: 12/10/2009
ckniffin: 11/19/2009
ckniffin: 11/12/2009
terry: 7/24/2003
carol: 6/24/2003
ckniffin: 6/20/2003
ckniffin: 6/19/2003
carol: 5/15/2003
terry: 1/24/2002
mcapotos: 10/2/2001
mcapotos: 9/24/2001
terry: 9/20/2001
cwells: 5/3/2001
mcapotos: 4/11/2001
mcapotos: 4/6/2001
terry: 4/5/2001
mcapotos: 5/10/2000
terry: 4/18/2000
carol: 1/5/1999
dholmes: 7/22/1998
carol: 7/16/1998
terry: 7/13/1998
terry: 3/24/1998
mark: 9/23/1997
terry: 9/19/1997
alopez: 6/11/1997
alopez: 3/19/1997
mark: 3/17/1997
mark: 12/26/1996
mark: 8/27/1996
terry: 7/24/1996
carol: 7/5/1996
terry: 7/3/1996
terry: 6/26/1995
mark: 6/7/1995
carol: 3/28/1994
mimadm: 2/19/1994
carol: 9/8/1993
carol: 6/4/1993