Alternative titles; symbols
HGNC Approved Gene Symbol: ITGB3
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:47,253,827-47,313,743 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.32 | {Myocardial infarction, susceptibility to} | 608446 | 3 | |
| Bleeding disorder, platelet-type, 24, autosomal dominant | 619271 | Autosomal dominant | 3 | |
| Glanzmann thrombasthenia 2 | 619267 | Autosomal recessive | 3 | |
| Purpura, posttransfusion | 3 | |||
| Thrombocytopenia, neonatal alloimmune | 3 |
The ITGB3 gene encodes glycoprotein IIIa (GP IIIa), the beta subunit of the platelet membrane adhesive protein receptor complex GP IIb/IIIa. The alpha subunit, GP IIb, is encoded by the ITGA2B gene (607759). The GP IIb/IIIa complex belongs to the integrin class of cell adhesion molecule receptors that share a common heterodimeric structure with alpha and beta subunits (summary by Bray et al., 1987 and Bajt et al., 1992).
Glycoprotein IIIa is also the beta subunit of 2 other integrins, fibronectin receptor (FNRB; 135630) and vitronectin receptor (193210), which have distinctive alpha subunits.
Zimrin et al. (1988) described the structure of GP IIIa deduced from an analysis of 4 kb of overlapping cDNA sequences isolated from a human erythroleukemia cell cDNA expression library. A continuous open reading frame encoding all 788 amino acids was present. The deduced amino acid sequence included a 26-residue N-terminal signal peptide, a 29-residue transmembrane domain near the C terminus, and 4 tandemly repeated cysteine-rich domains of 33 to 38 residues. Zimrin et al. (1988) found 38% similarity with the beta subunit of LFA1 (600065) and virtual identity with human endothelial cell GP IIIa. Northern blot analysis using RNA from both human erythroleukemia cells and endothelial cells showed 2 GP IIIa transcripts of 5.9 and 4.1 kb. However, erythroleukemia RNA, but not endothelial cell RNA, contained a transcript for GP IIb. This indicated that the GP IIIa-containing heterodimers in platelets and endothelial cells are not identical structures but are members of a subfamily within the family of human adhesion protein receptors sharing an identical beta subunit. Hynes (1987) proposed that there are 3 subfamilies within the family of human adhesion protein receptor heterodimers based on the number of different beta subunits. The platelet and endothelial cell heterodimers use GP IIIa as the beta subunit; the leukocyte heterodimers contain a beta subunit with a molecular mass of 95 kD that is homologous to GP IIIa but is clearly a different protein (600065); and the fibronectin receptors contain a beta subunit that appears to be analogous to band 3 of integrin (135630). Burk et al. (1988) described a RFLP of the GP3A gene.
Rosa et al. (1988) derived cDNAs for platelet GP IIIa peptide from a cDNA library which was constructed by use of an RNA purified from human erythroleukemia cells. The sequence matched a previously reported endothelial cell cDNA sequence except for 8 nucleotides. Five of these were silent changes consistent with genetic polymorphism.
Lanza et al. (1990) isolated genomic clones for the beta subunit of the fibronectin receptor. Of the 8 splice sites identified in FNRB, 6 occurred at the same amino acid residue as in GP3A. They interpreted these results as indicating a common evolutionary origin of GP3A and FNRB within the integrin family.
Lanza et al. (1990) demonstrated that the GP3A gene has 14 exons. The 3-prime exon is larger than 1,700 nucleotides and contains the 3-prime untranslated region.
Weiss et al. (2006) stated that the ITGB3 gene contains 15 exons and spans 60 kb.
Crystal Structure
Xiong et al. (2001) determined the crystal structure of the extracellular portion of integrin alpha-V-beta-3 at 3.1-angstrom resolution. Its 12 domains assemble into an ovoid head and 2 tails. In the crystal, alpha-V-beta-3 is severely bent at a defined region in its tails, reflecting an unusual flexibility that may be linked to integrin regulation. Xiong et al. (2002) determined the crystal structure of the extracellular segment of integrin alpha-V-beta-3 in complex with a cyclic peptide presenting the arg-gly-asp sequence. The ligand binds at the major interface between the alpha-V and beta-3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes were observed in the presence of ligand. The tertiary rearrangements take place in beta-A, the ligand-binding domain of beta-3; in the complex, beta-A acquires 2 cations, 1 of which contacts the ligand asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alpha-V relative to beta-3.
Xiao et al. (2004) defined with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin alpha-IIb-beta-3. Allostery in the beta-3 I domain alters 3 metal binding sites, associated loops, and alpha-1- and alpha-7-helices. Piston-like displacement of the alpha-7-helix causes a 62-degree reorientation between the beta-3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper beta-3 leg causes a 70-angstrom separation between the knees of the alpha and beta legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.
Rosa et al. (1988) localized the GP3A gene to chromosome 17 by hybridization to DNA from sorted chromosomes and by hybridization to DNA from mouse-human somatic hybrids.
Letellier et al. (1988) demonstrated linkage between the platelet-specific alloantigens Pl(A) and BAK, an epitope of GP IIb, and showed linkage disequilibrium in unrelated Caucasian subjects. By somatic cell hybrid and in situ hybridization studies, Sosnoski et al. (1988) found close physical location of the GP2B and GP3A genes in the segment 17q21-q23. Because of close physical proximity of the genes with resulting linkage disequilibrium, the authors suggested that it may be difficult to use RFLPs in family studies to assign the defect through either the GP2B or the GP3A gene in cases of thrombasthenia. Bray et al. (1988) demonstrated that both GP2B and GP3A are situated close to the TK1 gene (188300) on chromosome 17 and, furthermore, that GP2B and GP3A are physically linked within the same 260-kb pulsed field gel electrophoresis (PFGE) fragment. The findings suggested that GP2B is located on the 3-prime side of GP3A. Coordinate expression of these 2 genes may depend on physical proximity.
Van Cong et al. (1989) assigned the GP3A gene to chromosome 17 by somatic cell hybridization and to 17q21.1-q21.3 by in situ hybridization. By genetic linkage studies using multiple DNA markers in the 17q12-q21 region, Anderson et al. (1993) placed the GP3A gene on the genetic map of the region.
In a study of large kindreds with mutations in either ITGA2B or ITGB3, Thornton et al. (1999) developed a genetic linkage map between the THRA1 (190120) and ITGB3 genes as follows: cen--THRA1--BRCA1 (113705)--D17S579/ITGA2B--ITGB3--qter, with a distance of 1.3 cM between ITGA2B and ITGB3, and the 2 genes being oriented in the same direction. PFGE genomic and YAC clone analysis showed that the ITGB3 gene is distal and 365 kb or more upstream of ITGA2B. Additional restriction mapping showed that ITGA2B is linked to the EPB3 gene (SLC4A1; 109270), and ITGB3 to the HOX2B gene (HOXB6; 142961). Further analysis confirmed that the EPB3 gene is approximately 110 kb downstream of the ITGA2B gene. Sequencing the region surrounding the ITGA2B gene showed that the granulin gene (GRN; 138945) is located approximately 18 kb downstream to ITGA2B. Thornton et al. (1999) found that this organization is conserved in the murine sequence. These studies showed that the ITGA2B and ITGB3 genes are not closely linked, with ITGA2B flanked by nonmegakaryotic genes, and implied that the genes are unlikely to share common regulatory domains during megakaryopoiesis.
The GP IIb/IIIa complex mediates platelet aggregation by acting as a receptor for fibrinogen. The complex also acts as a receptor for von Willebrand factor and fibronectin (Prandini et al., 1988).
Lefkovits et al. (1995) reviewed the role of platelet glycoprotein IIb/IIIa receptors and their agonists in cardiovascular medicine. Since this receptor is involved in platelet aggregation, which is the final common pathway of platelet plug formation, the study of receptor inhibitors was considered a logical pharmaceutical strategy.
Stupack et al. (2001) demonstrated that cells adherent within a 3-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the beta subunit cytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Stupack et al. (2001) demonstrated that unligated integrin or beta-integrin tails recruit caspase-8 (601763) to the membrane, where it becomes activated in a death receptor-independent manner. Integrin ligation disrupts this integrin-caspase-containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.
While studying thrombus formation in mice lacking CD40L (300386), Andre et al. (2002) observed that recombinant soluble CD40L (rsCD40L) carrying a mutation changing the KGD motif sequence to KGE failed to restore thrombus stability. Flow cytometric analysis demonstrated that rsCD40L binds to activated platelets of wildtype as well as of CD40 (109535) -/- mice but that this binding can be inhibited by a peptide interfering with GP IIb/IIa binding. Plate-binding analysis indicated specific saturable binding of rsCD40L for GP IIb/IIa. Fluorescence microscopy showed that human platelets spread on but did not adhere to an rsCD40L-coated glass surface only in the absence of an inhibitor of ITGA2B/ITGB3. Andre et al. (2002) concluded that CD40L is a GP IIb/IIa ligand.
Transmembrane helices of integrin alpha and beta subunits have been implicated in the regulation of integrin activity. Li et al. (2003) showed that 2 mutations, gly708 to asn and met701 to asn, in the transmembrane helix of the beta-3 subunit enabled integrin alpha-IIB/beta-3 to bind soluble fibrinogen constitutively. Further characterization of the gly708-to-asn mutant revealed that it induced alpha-IIB/beta-3 clustering and constitutive phosphorylation of focal adhesion kinase (600758). This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. The findings of Li et al. (2003) suggested that homomeric associations involving transmembrane domains provide a driving force for integrin activation and suggested a structural basis for the coincidence of integrin activation and clustering.
In a patient with features of Glanzmann thrombasthenia and leukocyte adhesion deficiency-1 (116920), McDowall et al. (2003) identified a novel form of integrin dysfunction involving ITGB1 (135630), ITGB2 (600065), and ITGB3. ITGB2 and ITGB3 were constitutively clustered. Although all 3 integrins were expressed on the cell surface at normal levels and were capable of function following extracellular stimulation, they could not be activated via the 'inside-out' signaling pathways.
Mechanical forces on matrix-integrin-cytoskeleton linkages are crucial for cell viability, morphology, and organ function. The production of force depends on the molecular connections from extracellular-matrix-integrin complexes to the cytoskeleton. The minimal matrix complex causing integrin-cytoskeleton connections is a trimer of fibronectin's (135600) integrin-binding domain FNIII7-10. Jiang et al. (2003) reported a specific, molecular slip bond that was repeatedly broken by a force of 2 pN at the cellular loading rate of 60 nm/second; this occurred with single trimer beads but not with the monomer. Talin-1 (186745), which binds to integrins and actin filaments in vitro, is required for the 2-pN slip bond and rapid cytoskeleton binding. Furthermore, Jiang et al. (2003) showed that inhibition of fibronectin binding to alpha-v-beta-3 integrin and deletion of beta-3 markedly decreased the 2-pN force peak. They suggested that talin-1 initially forms a molecular slip bond between closely packed fibronectin-integrin complexes and the actin cytoskeleton, which can apply a low level of force to fibronectin until many bonds form or a signal is received to activate a force response.
Faccio et al. (2003) retrovirally transduced ITGB3 -/- osteoclast precursors with chimeric colony-stimulating factor-1 receptor (CSF1R; 164770) constructs containing various cytoplasmic domain mutations and found that CSF1R tyr697 was required for normalization of osteoclastogenesis and ERK activation (see 176948). Overexpression of FOS (164810) normalized the number of ITGB3 -/- osteoclasts in vitro but not their ability to resorb dentin. Faccio et al. (2003) concluded that whereas CSF1R and alpha-V-beta-3 integrin collaborate in the osteoclastogenic process through shared activation of the ERK/FOS signaling pathway, the integrin is essential for matrix degradation.
Wang et al. (2003) showed that epidermal growth factor receptor (EGFR; 131550) serves as a receptor for cytomegalovirus (CMV). Given the broad tropism of CMV, Wang et al. (2005) sought additional receptors. Antibody-mediated infection-blocking experiments indicated that CMV also uses alpha-V-beta-3 integrin, but not other integrins, as a coreceptor. Upon infection, CMV glycoproteins gB and gH independently bound to EGFR and alpha-V-beta-3, respectively, to initiate viral entry and signaling. CMV infection induced phosphorylation of beta-3 and EGFR and activated SRC (190090) and PI3K (see PIK3CG; 601232) signaling pathways, respectively. Activated alpha-V-beta-3 translocated to lipid rafts, where it interacted with activated EGFR to induce coordinated signaling. This coordination was essential for viral entry, RhoA (ARHA; 165390) downregulation, stress fiber disassembly, and viral nuclear trafficking.
Raymond et al. (2005) noted that crystal structure and electron microscopy analyses had demonstrated dramatically different active and inactive conformations of alpha-V-beta-3 integrin. Manganese ions direct the conformation of the extended, activated form, which binds ligands through adjacent globular heads, whereas calcium ions direct the bent, inactive structure, which is folded in a manner that masks the ligand-binding site (Takagi et al., 2002). By mutation analysis, Raymond et al. (2005) found that pathogenic forms of hantavirus required asp39 in the PSI domain of beta-3 for infection. Infection of cells by pathogenic strains was enhanced by calcium and inhibited by manganese, suggesting that hantavirus interacts with apical PSI domains exposed on the surface of bent alpha-V-beta-3 integrins. Cells expressing the extended form of alpha-V-beta-3 were resistant to hantavirus infection, whereas cells expressing the bent form were susceptible. Raymond et al. (2005) proposed that viral interaction with inactive integrin restricts alpha-V-beta-3 functions that regulate vascular permeability.
Gong et al. (2010) found that the heterotrimeric guanine nucleotide-binding protein G-alpha-13 (604406) directly binds to the integrin beta-3 cytoplasmic domain and that G-alpha-13-integrin interaction is promoted by ligand binding to the integrin alpha-IIb (607759)-beta-3 and by GTP loading of G-alpha-13. Interference of G-alpha-13 expression or a myristoylated fragment of G-alpha-13 that inhibited interaction of alpha-IIb-beta-3 with G-alpha-13 diminished activation of protein kinase c-Src (124095) and stimulated the small guanosine triphosphatase RhoA (165390), consequently inhibiting cell spreading and accelerating cell retraction. Gong et al. (2010) concluded that integrins are noncanonical G-alpha-13-coupled receptors that provide a mechanism for dynamic regulation of RhoA.
Shen et al. (2013) demonstrated that G-alpha-13 and talin (186745) bind to mutually exclusive but distinct sites within the integrin beta-3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signaling and also ligand-induced integrin activation, but is not required for outside-in signaling. Integrin ligation induces transient talin dissociation and G-alpha-13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signaling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of G-alpha-13-integrin interaction selectively abolishes outside-in signaling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Shen et al. (2013) concluded that they discovered a mechanism for the directional switch of integrin signaling and, on the basis of this mechanism, designed a potent antithrombotic drug that does not cause bleeding.
Platelet-specific Antigens and Alloimmune Thrombocytopenia
There are 2 serologically defined allelic forms of the platelet-specific alloantigen Pl(A): Pl(A1) and Pl(A2), both of which have been localized to the GP IIIa molecule. The gene frequency for Pl(A1) is about 85% and for Pl(A2) about 15% in U.S. Caucasians (Newman et al., 1989). Newman et al. (1989) demonstrated that the Pl(A1) and Pl(A2) diallelic difference depends on the presence of leucine or proline, respectively, as amino acid 33 of the GP IIIa molecule (see 173470.0006). The amino acid substitution was produced by a C-to-T polymorphism at base 196, which created a unique restriction enzyme cleavage site in the Pl(A2) cDNA. The platelet antigen system is of clinical significance because alloimmunization can occur. Maternofetal incompatibility in relation to Pl(A) is responsible for neonatal alloimmune thrombocytopenia (NAIT). Immunization against Pl(A1) is responsible for posttransfusion thrombocytopenia, a disorder limited almost entirely to women who have acquired sensitization during pregnancy.
Shibata et al. (1986) reported a novel platelet antigen, YUK(b), involved in a case of neonatal alloimmune thrombocytopenia. They considered this antigen to be a product of an allele of the YUK gene, another allele of which codes for YUK(a), which had been involved in other cases of neonatal alloimmune thrombocytopenia. YUK(a) and YUK(b) antigens are not expressed on platelets from patients with Glanzmann thrombasthenia, suggesting that these antigens are present on platelet glycoprotein IIb and/or IIIa. The gene frequencies for YUK(a) and YUK(b) in the Japanese population were estimated to be 0.0083 and 0.9917, respectively. YUK(b) and YUK(a) are the same as PEN(a) and PEN(b), respectively. See 173470.0005 for a description of the molecular basis of this polymorphism. Furihata et al. (1987) determined that the Pen(a) alloantigen is associated with GP IIIa but is distinct from Pl(A). (See also NOMENCLATURE below).
Kekomaki et al. (1991) concluded that a 50-kD cysteine-rich region of GP IIIa is a frequent target of autoantibodies in idiopathic thrombocytopenia.
Transplanted organs, particularly livers and kidneys, carry passenger lymphocytes that can transmit autoimmune diseases or initiate alloimmune disorders in the recipient. West et al. (1999) described 3 unrelated patients with severe alloimmune thrombocytopenia that developed as a result of antibodies against the HPA-1a (Pl(A1)) alloantigen. In these patients the thrombocytopenia was refractory to all medical maneuvers except the transfusion of HPA-1a-negative platelets. In 1 patient the thrombocytopenia contributed to death. In another patient the thrombocytopenia was cured by splenectomy, and in the third patient the thrombocytopenia resolved after an episode of severe graft rejection. All 3 organs were from the same donor, the kidney in 2 cases and the liver in the third. The donor was homozygous for HPA-1b; the 3 recipients were homozygous for HPA-1a. The results of nested PCR with a set of primers specific for the HLA-DR4 allele showed that DNA from the donor was present in the spleen of the patient who responded to splenectomy, but not in peripheral blood.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Glanzmann Thrombasthenia 2
In Glanzmann thrombasthenia (see GT2, 619267), both GP IIIa and the platelet allotype are deficient or lacking. Kunicki et al. (1981) concluded that the lack of expression of the Pl(A1) antigen on thrombasthenic platelets results from the decrease or absence of GP IIIa.
In a child with Glanzmann thrombasthenia-2, Bray and Shuman (1989, 1990) found compound heterozygosity for a defect in GP IIIa. The child had inherited from the father a gene with a large rearrangement detected by Southern blot analysis.
Newman et al. (1991) demonstrated that the form of Glanzmann thrombasthenia frequent in Iraqi Jews is due to a truncated GP IIIa lacking a transmembrane domain as a result of an 11-bp deletion within exon 12 of the ITGB3 gene (173470.0014), whereas the form of the disease frequent in Arabs in Israel is due to a 13-bp deletion that spans the intron/exon boundary of exon 4 of the ITGA2B gene (607759.0002).
Rosenberg et al. (1997) stated that most mutations in the ITGA2B and ITGB3 genes are point mutations: 10 in ITGB3 and 12 in ITGA2B. In addition, 9 are small or large rearrangements: 5 in ITGB3 and 4 in ITGA2B. They added a large deletion mutation of the ITGB3 gene (173470.0011) to the list.
In a patient with Glanzmann thrombasthenia, Jin et al. (1996) identified homozygosity for a mutation upstream of the GP IIIa exon 9 splice donor site. Patient platelet GP IIIa transcripts lacked exon 9 despite normal DNA sequence in all of the cis-acting sequences known to regulate splice site selection. In vitro analysis of transcripts generated from mini-gene constructs demonstrated that exon skipping occurred only when the mutation was cis to a polymorphism 116 bp upstream, providing precedence that 2 sequence variations in the same exon which do not alter consensus splice sites and do not generate missense or nonsense mutations can affect splice site selection. The mutant transcript resulted from utilization of a cryptic splice acceptor site and returned the open reading frame. These data supported the hypothesis that pre-mRNA secondary structure and allelic sequence variants can influence splicing and provided new insight into the regulated control of RNA processing. In addition, haplotype analysis suggested that the patient had 2 identical copies of chromosome 17. Markers studied on 3 other chromosomes suggested that this finding was not due to consanguinity. Jin et al. (1996) stated that the restricted phenotype in this patient may provide information regarding the expression of potentially imprinted genes on chromosome 17. Jin et al. (1996) ruled out the possibility of a large gene deletion. They believed this to be the first reported example of chromosomal 17 uniparental disomy, in this case maternal disomy. The patient's father was not available for study to definitively eliminate the possibility of consanguinity in this case.
Among 24 patients with Glanzmann thrombasthenia and 2 asymptomatic carriers of the disorder, Jallu et al. (2010) identified 20 different mutations in the ITGA2B gene (see, e.g., 607759.0015-607759.0016) in 18 individuals and 10 different mutations in the ITGB3 gene (see, e.g., 173470.0016-173470.0017) in 8 individuals. There were 17 novel mutations described. Four mutations in the ITGB3 gene were examined for pathogenicity and all were found to decrease cell surface expression of the IIb/IIIa complex, consistent with the severe type I phenotype. One in particular, K253M (173470.0016), defined a key role for the lys253 residue in the interaction of the alpha-IIb propeller and the beta-I domain of IIIa, and loss of lys253 would interrupt complex formation.
Platelet-Type Bleeding Disorder 24, Autosomal Dominant
In 5 members of a family with autosomal dominant platelet-type bleeding disorder-24 manifest as congenital macrothrombocytopenia (BDPLT24; 619271), Ghevaert et al. (2008) identified a heterozygous mutation in the ITGB3 gene (D723H; 173470.0018). Molecular modeling indicated that the mutation changed the electrostatic surface potential, consistent with the disruption of a conserved salt bridge with R995 in the ITGA2B gene (607759). In vitro functional expression assays in CHO cells showed that the mutant protein was constitutively active. The mutant protein also led to the formation of large proplatelet-like protrusions in CHO cells and in patient megakaryocytes in the presence of fibrinogen. The findings suggested that constitutive partial activation by the mutant receptor caused abnormal sizing of platelets during formation, resulting in thrombocytopenia due to increased platelet turnover. GPIIb/IIIa expression on platelets was normal, and none of the affected individuals had bleeding abnormalities; the defect in the proband was an incidental finding.
In affected members of 2 unrelated Italian families with autosomal dominant BDPLT24, Gresele et al. (2009) identified a heterozygous mutation in the ITGB3 gene (173470.0019). Haplotype analysis suggested a founder effect. Clinical features included lifelong bleeding tendency, particularly mucosal bleeding, and macrothrombocytopenia.
Kobayashi et al. (2013) identified a heterozygous mutation in the ITGB3 gene (L718P; 173470.0020) in affected members of a 4-generation Japanese family with BDPLT24. Studies of patient platelets showed decreased expression of the GPIIb/IIIa complex and evidence of spontaneous partial activation, including increased PAC-1 binding and increased fibrinogen binding potential. In CHO cells, the mutation promoted the generation of proplatelet-like protrusions by downregulation of RhoA (165390) activity. The findings suggested that this mutation contributes to thrombocytopenia through a gain of function.
Heritability of Normal Blood Parameters
In a study of 2,413 participants in the Framingham Heart Study, O'Donnell et al. (2001) found evidence for the heritability of platelet aggregation responses to epinephrine and ADP and collagen lag time. The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4 to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20 to 30%. However, the Pl(A2) variant of platelet glycoprotein IIIa and the fibrinogen HindIII beta-148 polymorphism (134830.0014) contributed less than 1% of the overall variance.
In 567 Hutterite individuals, Weiss et al. (2004) found suggestive evidence for linkage between whole blood serotonin and the ITGB3 gene: genomewide linkage analysis yielded a lod score of 1.87 near ITGB3, and allele-specific association tests showed that the leu33 allele was associated with lower levels of serotonin (pointwise p = 0.000098). Weiss et al. (2004) noted that more than 99% of whole blood serotonin is contained in the platelet, and whole blood serotonin correlated with serotonin per unit mass of platelet protein. The authors suggested that polymorphisms in the ITGB3 gene may act as a recessive quantitative trait locus (QTL) for whole blood serotonin. By sex stratification analysis of the data obtained by Weiss et al. (2004), Weiss et al. (2005) found that the serotonin QTL associated with the ITGB3 gene influenced serotonin blood levels only in males.
Association with Autism
See 610676 for a discussion of a possible association between autism susceptibility and variation in the ITGB3 gene.
According to a report on nomenclature of platelet-specific alloantigens, HPA-1 is the designation for Zw and Pl(A), and HPA-4 is the designation for Pen and Yuk (von dem Borne and Decary, 1990). The allele of high frequency is called 'a' and that of low frequency 'b.' Newman (1994) pointed out that unfortunately the HPA nomenclature system was conceived just before the discovery of the molecular basis of platelet membrane GP polymorphisms, and he illustrated the fact that it does not seem to be capable, in its original form, of serving the nomenclature needs while remaining scientifically accurate. For illustration purposes, he discussed the HPA nomenclature of GP IIIa, because it represented the 'worst case scenario.' He provided an ingenious diagram in which it could be seen that the HPA-1a, HPA-4a, HPA-7a, HPA-6a, and HPA-8a antigens are actually 5 different names for the same molecular species, i.e., a single GP IIIa allele with a gene frequency of 0.85 in the Caucasian population and the amino acid constitution leu33-arg143-pro407-arg489-arg636.
Newman (1994) proposed a modified HPA nomenclature in which the 5 identical allelic forms of GP IIIa have only 1 HPA designation, HPA-1a. A departure from the HPA nomenclature used GP IIIa as the designation for the most frequent allele and the alloantigen it encodes, whereas Pl(A2) becomes pro33-GP IIIa; Pen(b), gln143-GP IIIa; Mo(a), ala407-GP IIIa; Ca/Tu(a), gln489-GP IIIa; and Sr(a), cys636-GP IIIa.
Beta-3 integrins have been implicated in a wide variety of functions, including platelet aggregation and thrombosis and implantation, placentation, angiogenesis, bone remodeling, and tumor progression. Glanzmann thrombasthenia can result from defects in the genes for either the alpha-IIb (607759) or the beta-3 subunit. To develop a mouse model of Glanzmann thrombasthenia and to further studies of hemostasis, thrombosis, or other suggested roles of beta-3 integrins, Hodivala-Dilke et al. (1999) generated a strain of beta-3 null mice. The mice were viable and fertile, and showed all the cardinal features of Glanzmann thrombasthenia. Implantation appeared to be unaffected, but placental defects did occur and led to fetal mortality. Postnatal hemorrhage led to anemia and reduced survival.
Reynolds et al. (2002) reported that mice lacking beta-3 integrins or both beta-3 and beta-5 integrins not only support tumorigenesis but have enhanced tumor growth as well. The tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta-3 nor beta-5 integrins are essential for neovascularization. Reynolds et al. (2002) also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF; 192240) are augmented significantly in the absence of beta-3 integrins. Reynolds et al. (2002) found no evidence that the expression or functions of other integrins were altered as a consequence of the beta-3 deficiency, but did observe elevated levels of VEGF receptor-2 (191306) in beta-3 null-endothelial cells. Reynolds et al. (2002) concluded that alpha-5-beta-3 and alpha-5-beta-5 integrins are not essential for vascular development or pathologic angiogenesis.
Reynolds et al. (2005) found that mice lacking Itgb3 showed enhanced wound healing with reepithelialization complete several days earlier than in wildtype mice. The effect was due to increased Tgfb1 (190180) and enhanced dermal fibroblast infiltration into wounds of Itgb3-null mice. Specifically, Itgb3 deficiency was associated with elevated Tgfbr1 (190181) and Tgfbr2 (190182) expression, reduced Smad3 (603109) levels, sustained Smad2 (601366) and Smad4 (600993) nuclear localization, and enhanced Tgfb1-mediated dermal fibroblast migration. Reynolds et al. (2005) concluded that alpha-5-beta-3 integrin can control the rate of wound healing by suppressing Tgfb1-mediated signaling.
In a patient with Glanzmann thrombasthenia (GT2; 619267), Bajt et al. (1992) identified a G-to-A transition in the ITGB3 gene, resulting in an arg214-to-gln (R214Q) substitution. The patient's platelets failed to aggregate in response to stimuli. Bajt et al. (1992) concluded that the point mutation involved a putative ligand-binding domain of the beta-3 subunit.
The Cam variant of Glanzmann thrombasthenia (GT2; 619267) (Ginsberg et al., 1986) is an autosomal recessive hereditary disorder of the GP IIb-IIIa complex that is associated with the inability of this integrin to recognize macromolecular or synthetic peptide ligands. Loftus et al. (1990) determined that the disorder was due to a G-to-T transversion in the ITGB3 gene, resulting in an asp119-to-tyr (D119Y) substitution. Two affected sibs were studied.
In a patient with Glanzmann thrombasthenia (GT2; 619267), Lanza et al. (1992) found a C-to-T transition in exon D of ITGB3 resulting in an arg214-to-trp (R214W) substitution. The patient was a 19-year-old Caucasian female who from birth had had bleeding episodes consisting mainly of unprovoked bruising. She had a traumatic intracerebral hematoma at the age of 6 years. The parents, who were first cousins ('direct cousins'), were each heterozygous for the same mutation. The patient showed an absence of platelet aggregation to ADP, thrombin, and collagen, and a decreased clot retraction. Platelet fibrinogen was about 20% of normal. ADP-stimulated platelets bound markedly reduced amounts of soluble fibrinogen, and platelet adhesion to surface-bound fibrinogen was defective. The substitution involved an amino acid critical to the region of GP IIIa involved in the binding of fibrinogen. Arg214 in the protein encoded by the ITGB3 gene is substituted also in another form of Glanzmann thrombasthenia (173470.0001).
Chen et al. (1992) described a form of Glanzmann thrombasthenia (GT2; 619267) in which chemical and genetic analyses were consistent with the idea that the functional defect was due to a ser752-to-pro (S752P) substitution in the cytoplasmic domain of beta-3. This mutation was predicted to impair the coupling between cellular activation and upregulation of affinity of the alpha-IIb/beta-3 complex for fibrinogen. This appeared to be the first point mutation reported that affects integrin activation.
Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura
The Pen(a)/Pen(b) alloantigen system has been implicated in 2 clinical syndromes, neonatal alloimmune thrombocytopenic purpura and posttransfusion purpura. Wang et al. (1992) identified a 526G-A transition in the ITGB3 gene, resulting in an arg143-to-gln (R143Q) substitution that correlated with the Pen serologic phenotype. The polymorphic residue is located within the 63-amino acid region (residues 109-171) that interacts with the tripeptide sequence, RGD (arg-gly-asp), that is present in many adhesive protein ligands, including fibrinogen, fibronectin, and von Willebrand factor. Wang et al. (1992) found that the anti-Pen(a) alloantibodies could recognize only the arg143 recombinant form and anti-Pen(b) alloantibodies were reactive only with the gln143 isoform.
The molecular basis of the platelet-specific alloantigen system Pl(A) is a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a leu33-to-pro (L33P) substitution which corresponds to Pl(A1) and Pl(A2), respectively (Newman et al., 1989). Pl(A) is also known as alloantigen Zw.
Kim et al. (1995) determined the allelic frequencies of Pl(A1) and Pl(A2) in African Americans, whites, and Koreans living in the metropolitan Baltimore area.
Myocardial Infarction, Susceptibility to
Using a monoclonal antibody that specifically distinguished Pl(A1) from Pl(A2), Weiss et al. (1995) observed an unexpected high frequency of family members homozygous for the A2 allele in kindreds with a high prevalence of acute coronary events at a relatively young age (under 60 years). In a case-control study, Weiss et al. (1996) found that the A2 allele was 2.1 times more prevalent among 71 patients with myocardial infarction (see 608446) or unstable angina than among controls (39.4% vs 19.1%, respectively; P = 0.01). In a subgroup of patients whose disease began before the age of 60 years, the prevalence of the A2 allele was 50%, a value that was 3.6 times that among control subjects under 60 years of age (13.9%; P = 0.002), yielding an odds ratio (OR) of 2.8 for those with the A2 allele. In patients less than 60 years of age at the onset of disease, the OR was 6.2.
Goldschmidt-Clermont et al. (1996) reported without supporting data that the other major polymorphisms were not associated with myocardial infarction: Ko(a), Ko(b), Bak(a), Bak(b), Pen(a), Pen(b), Br(a), and Br(b).
Goldschmidt-Clermont et al. (1996) presented evidence that Sergei Grinkov, twice Olympic pairs figure skating gold medalist, was heterozygous for the A1/A2 polymorphism and suggested that this may have been related to his precocious coronary artery disease. Grinkov, aged 28, collapsed suddenly while training on the ice rink in Lake Placid, New York, and could not be resuscitated. Necropsy showed severe coronary artery disease and a recent (4- to 6-hour-old) anteroseptal myocardial infarction (MI). He had never sought medical attention for a heart problem. He was not a smoker, did not use drugs or medications, did not have hypertension or diabetes mellitus, his total cholesterol and lipid profiles were unremarkable, and he trained for several hours daily. Significantly, his father died suddenly at the age of 52 years. See the lay account by Grinkov's widow, Ekaterina Gordeeva (1996).
Goldschmidt-Clermont et al. (1999) genotyped 116 asymptomatic sibs (60 Caucasians, 56 Afro-Caribbeans) of patients with coronary heart disease manifested before the age of 60 years for the Pl(A) polymorphism. A control cohort consisted of 268 individuals (168 Caucasians, 100 Afro-Caribbeans) who were matched for race and geographic area but were free of coronary heart disease. The authors also characterized the sib cohort for other atherogenic and thrombogenic risk factors. The results supported the hypothesis that the prevalence of Pl(A2)-positive individuals is high in kindreds with premature coronary heart disease. Hence, like the established risk factors that tend to cluster in families with premature coronary heart disease and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GP IIIa may represent an inherited risk that promotes the thromboembolic complications of coronary heart disease. That these asymptomatic sibs had overall less-established risk factors than their Pl(A1) counterparts may provide an explanation for why they remained asymptomatic despite their Pl(A2) positivity.
In a cross-sectional study of patients with a history of myocardial infarction and in matched controls from the Finnish population, Pastinen et al. (1998) analyzed common variants of 8 genes implicated previously as risk factors for coronary heart disease or MI. The most common low density lipoprotein receptor (LDLR; 606945) mutations in Finland were also included in the analysis. Multiplex genotyping of the target genes was performed using a specific and efficient array-based minisequencing system. The 4G allele of the PAI1 (173360) gene (P less than 0.05) and the Pl(A2) allele of the glycoprotein IIIa gene (P less than 0.01) were associated with an increased risk of MI in the Finnish study population. They found that the combined effect of these risk alleles conferred a high risk for the development of MI (OR = 4.5, P = 0.001), which was particularly prominent in male subjects (OR = 6.4, P = 0.0005). The observation of 2 separate genes contributing an additive risk of developing MI exemplified the advantages of multiplex analysis of genetic variation.
Undas et al. (2001) reported studies in healthy, male, nonsmoking medical students aged 21 to 24 years using a controlled method for producing microvascular injury. They found that the Pl(A2) variant was associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury.
Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura
Pl(A) is the alloantigen most frequently implicated in syndromes of immune-mediated platelet destruction, particularly neonatal alloimmune thrombocytopenia and posttransfusion purpura (Newman et al., 1989).
Hip Fracture, Susceptibility to
Tofteng et al. (2007) analyzed the L33P polymorphism in 9,233 randomly selected Danish individuals, of whom 267 had a hip fracture (see 166710) during a 25-year follow-up period. Individuals homozygous for L33P had a 2-fold greater risk of hip fracture compared to noncarriers (p = 0.02), with risk confined primarily to postmenopausal women, in whom the hazard ratio was 2.6 after adjustment for age at menopause and use of hormone replacement therapy.
Neonatal Alloimmune Thrombocytopenia
In a case of neonatal alloimmune thrombocytopenia, Kroll et al. (1990) identified a private antigen on GP IIIa. Kuijpers et al. (1993) identified a 1267C-G transversion in the ITGB3 gene, resulting in a pro407-to-ala (P407A) substitution. The antigen was provisionally called 'Mo' after the name of the family. All family members, including those who were Mo antigen positive, were healthy; heterozygotes appeared to have no significant platelet dysfunction in vivo since none of them suffered from increased tendency to bleeding or thrombosis. One of 45 random healthy blood donors was found to be positive for the Mo antigen.
Simsek et al. (1993) found homozygosity for a splice mutation in the ITGB3 gene in a 29-year-old woman with Glanzmann thrombasthenia (GT2; 619267), the offspring of first-cousin parents. From childhood she had suffered from a severe hemorrhagic diathesis, manifesting as epistaxis, gingival bleeding, and menorrhagia and requiring regular transfusions of whole blood and/or platelets. A G-to-T transversion eliminated the GT splice donor site at the boundary of exon i with intron i. Both parents were heterozygous and the proposita was homozygous for the mutation which resulted in skipping of exon i.
Neonatal Alloimmune Thrombocytopenia
In a Filipino family living in Canada, Wang et al. (1993) demonstrated that neonatal alloimmune thrombocytopenia, resulting from a platelet alloantigen termed Ca, had its basis in a 1564G-A transition in the ITGB3 gene, resulting in an arg489-to-gln (R489Q) substitution. At least 3 different codons resulting in the wildtype arg489 were identified in the general population: CGG (63%), CGA (37%), and CGC (less than 1%). Wang et al. (1993) demonstrated that the Ca alloantigen is identical to the Tu platelet alloantigen defined in the Finnish population (Kekomaki et al., 1993).
In a Chinese patient with Glanzmann thrombasthenia (GT2; 619267), Chen et al. (1993) identified a cys374-to-tyr (C374Y) substitution in the product of the ITGB3 gene.
In 3 unrelated Iraqi-Jewish families with Glanzmann thrombasthenia (GT2; 619267), Rosenberg et al. (1997) identified an 11.2-kb deletion between an Alu sequence in intron 9 and exon 13 in the GP3A gene. They showed that in the general Iraqi-Jewish population living in Israel, the frequency of heterozygotes for an 11-bp deletion (173470.0014) is 1 in 114 and that for the 11.2-kb deletion is less than 1 in 700. Haplotype analyses indicated that each mutation originated in a distinct founder.
Wang et al. (1997) studied a thrombasthenic variant in a patient whose platelets failed to aggregate in response to physiologic agonists (GT2; 619267), despite the fact that they contained abundant levels of alpha-IIb/beta-3 on their surface. Binding of soluble fibrinogen or fibrinogen mimetic antibodies to patient's platelets did not occur, except in the presence of ligand-induced binding site antibodies that transformed the patient's integrin complex into an active conformation from outside the cell. Sequence analysis revealed a 2268C-T substitution in the ITGB3 gene that resulted in an arg724-to-ter (R724X) substitution, producing a truncated protein containing only the first 8 of the 47 amino acids normally present in the cytoplasmic domain. Functional analysis of both the patient's platelets and Chinese hamster ovary cells stably expressing this truncated integrin revealed that the complex with the mutation was able to mediate binding to immobilized fibrinogen, although downstream events, including cytoskeletally-mediated cell spreading and tyrosine phosphorylation of focal adhesion kinase (600758), failed to occur. The studies of Wang et al. (1997) established the importance of the membrane-distal portion of the integrin beta-3 cytoplasmic domain in bidirectional transmembrane signaling in human platelets, and the role of integrin signaling in maintaining normal hemostasis in vivo. The patient was a 10-year-old African American with normal platelet counts but with severe bleeding from birth. The bleeding time was greater than 20 minutes.
Ferrer et al. (1998) described a novel mutation of the ITGB3 gene in a 20-year-old Caucasian woman clinically diagnosed as having Glanzmann thrombasthenia (GT2; 619267) when referred with a history of mucocutaneous bleeding episodes and unprovoked bruising that started soon after birth, as well as copious menstrual hemorrhages. The parents were unaffected and not known to be related. The patient was found to be homozygous for a 1846G-T transversion in exon 11 of the ITGB3 gene, resulting in a glu616-to-ter (E616X) substitution. Cytometric and immunochemical analysis indicated that platelet GP IIb-IIIa was absent in the proband but present at normal levels in the heterozygous relatives. Pulse-chase and immunoprecipitation analysis of GP IIb-IIIa complexes in cells transiently cotransfected with cDNAs encoding normal GP IIb and (T1846)GP IIIa showed neither maturation of GP IIb nor complex formation and surface exposure of GPIIb-delGPIIIa. These observations indicated that the sequence from glu616 to thr762 in GP IIIa is essential for heterodimerization with GP IIb. PCR-based analysis demonstrated the presence of normal levels of full-length GP IIIa mRNA in the proband and in heterozygous relatives. In addition, a shortened transcript, with a 324-nucleotide deletion resulting from in-frame skipping of exons 10 and 11, was detectable upon reamplification of the DNA. Thus, unlike other nonsense mutations, (T1846)GP IIIa does not lead to abnormal processing or reduction in the number of transcripts with the termination codon.
In 6 unrelated Iraqi-Jewish patients with Glanzmann thrombasthenia (GT2; 619267), Newman et al. (1991) identified an 11-bp deletion in exon 12 of the GP3A gene.
In a study of 40 families with Glanzmann thrombasthenia (GT2; 619267) in southern India, Peretz et al. (2006) found that 12 families carried a 428T-G transversion in exon 4 of the ITGB3 gene, resulting in a leu143-to-trp substitution (L143W; L117W in the mature glycoprotein). Evidence of a founder effect was detected. This mutation had been described by Basani et al. (1997).
In a patient with Glanzmann thrombasthenia (GT2; 619267), Jallu et al. (2010) identified compound heterozygosity for 2 mutations in the ITGB3 gene: an 836A-T transversion in exon 6, resulting in a lys253-to-met (K253M) substitution in the mature protein, and G221D (173470.0017). Both mutations are located in the beta-I domain. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation prevented normal GPIIb/IIIa complex expression on the cell surface consistent with a severe type 1 phenotype. However, specific antibodies detected some residual expression of the IIIa protein. Structural and free energy analyses of the IIb/IIIa complex showed that the side chain of lys253 protrudes from the IIIa beta-I domain and is involved with the beta-propeller of alpha-IIb (607759). The K253M mutation would interrupt this interaction.
In a patient with Glanzmann thrombasthenia (GT2; 619267), Jallu et al. (2010) identified compound heterozygosity for 2 mutations in the ITGB3 gene: a 740G-A transition in exon 5, resulting in a gly221-to-asp (G221D) substitution in the mature protein, and K253M (173470.0016). Both mutations are located in the beta-I domain. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation prevented normal GPIIb/IIIa complex expression on the cell surface consistent with a severe type 1 phenotype. However, specific antibodies detected some residual expression of the IIIa protein. Jallu et al. (2010) postulated that the mutation interferes with correct folding of the protein.
In 5 members of a family with autosomal dominant platelet-type bleeding disorder-24 manifest as congenital macrothrombocytopenia (BDPLT24; 187800), Ghevaert et al. (2008) identified a heterozygous c.2245G-C transversion in exon 14 of the ITGB3 gene, resulting in an asp723-to-his (D723H) substitution in the membrane proximal cytoplasmic segment of the protein. Molecular modeling indicated that the mutation changed the electrostatic surface potential, consistent with the disruption of a conserved salt bridge with R995 in the ITGA2B gene (607759). The D723H mutation was not found in unaffected family members or in 1,639 controls. In vitro functional expression assays in CHO cells showed that the mutant protein was constitutively active. There was spontaneously increased binding of the PAC-1 antibody, which specifically recognizes the activated form of the GPIIb/IIIa complex, as well as increased adhesion to von Willebrand factor (VWF) in static conditions and increased binding to fibrinogen under shear stress compared to wildtype. The mutant protein also led to the formation of large proplatelet-like protrusions in CHO cells and in patient megakaryocytes in the presence of fibrinogen. The findings suggested that constitutive partial activation of the mutant receptor caused abnormal sizing of platelets during formation, resulting in thrombocytopenia due to increased platelet turnover. GPIIb/IIIa expression on platelets was normal, and none of the affected individuals had bleeding abnormalities; the defect in the proband was an incidental finding.
In affected members of 2 unrelated Italian families with autosomal dominant platelet-type bleeding disorder-24 (BDPLT24; 619267), Gresele et al. (2009) identified a heterozygous G-to-C transversion in intron 13 of the ITGB3 gene (c.2134+1G-C), resulting in an in-frame 120-bp deletion in exon 13, with loss of 40 residues from the extracellular domain (asp647_glu686del). The mutation segregated with the phenotype in the family and was not found in 150 unrelated controls. Haplotype analysis suggested a founder effect. Clinical features included lifelong bleeding tendency, particularly mucosal bleeding, and macrothrombocytopenia. Patient platelets showed decreased expression of the GPIIb/IIIa complex. Functional studies showed several abnormalities, including impaired platelet aggregation to physiologic agonists but not to ristocetin, normal clot retraction, reduced fibrinogen binding and reduced expression of activated GPIIb/IIIa upon stimulation, normal platelet adhesion to immobilized fibrinogen but reduced platelet spreading, and decreased tyrosine phosphorylation, indicating defective outside-in signaling. Spontaneous aggregation was absent. The concomitant presence of both the normal and a mutant ITGB3 allele in patient platelet lysates suggested a loss-of-function hypothesis with a dominant-negative effect.
In a Spanish woman with platelet-type bleeding disorder-24 (BDPLT24; 619267), Jayo et al. (2010) identified a de novo heterozygous c.2231T-C transition in the ITGB3 gene, resulting in a leu718-to-pro (L718P) substitution in the membrane proximal region of the cytoplasmic domain, which plays a role in maintaining the GPIIb/IIIa complex in a low affinity state. The mutation was not found in more than 50 control DNA samples and was not present in the unaffected parents. Immunofluorescence studies showed that mutant protein was retained intracellularly, consistent with reduced surface expression of the GPIIb/IIIa complex on patient platelets. Cells transfected with the mutation showed increased PAC-1 binding, increased fibrinogen binding, and increased cell aggregation compared to controls, suggesting that the mutation causes constitutive activation of the integrin complex. Fibrinogen-adherent cells showed a peculiar spreading phenotype with long protrusions. Cells with the mutation showed an abnormal pattern of integrin clusters and integrin-free patches that was associated with disruption of ordered lipid domains within the plasma membrane. This aberrant distribution was thought to result in altered outside-in signaling and to cause abnormal platelet adhesion.
Kobayashi et al. (2013) identified a heterozygous L718P substitution in affected members of a 4-generation Japanese family with BDPLT24. The mutation was identified by exome sequencing, was not found in control databases, and segregated with the disorder in the family. Studies of patient platelets showed decreased expression of the GPIIb/IIIa complex and evidence of spontaneous partial activation, including increased PAC-1 binding and increased fibrinogen binding potential. After treatment with the agonist ADP, patient platelets did not show significantly increased fibrinogen binding potential compared to controls, suggesting that they cannot be fully activated in the presence of such signals. In CHO cells, the mutation promoted the generation of proplatelet-like protrusions by downregulation of RhoA (165390) activity. The findings suggested that this mutation contributes to thrombocytopenia through a gain of function.
Anderson, L. A., Friedman, L., Osborne-Lawrence, S., Lynch, E., Weissenbach, J., Bowcock, A., King, M.-C. High-density genetic map of the BRCA1 region of chromosome 17q12-q21. Genomics 17: 618-623, 1993. [PubMed: 8244378] [Full Text: https://doi.org/10.1006/geno.1993.1381]
Andre, P., Prasad, K. S. S., Denis, C. V., He, M., Papalia, J. M., Hynes, R. O., Phillips, D. R., Wagner, D. D. CD40L stabilizes arterial thrombi by a beta(3) integrin-dependent mechanism. Nature Med. 8: 247-252, 2002. [PubMed: 11875495] [Full Text: https://doi.org/10.1038/nm0302-247]
Bajt, M. L., Ginsberg, M. H., Frelinger, A. L., III, Berndt, M. C., Loftus, J. C. A spontaneous mutation of integrin alpha(IIb)-beta(3) (platelet glycoprotein IIb-IIIa) helps define a ligand binding site. J. Biol. Chem. 267: 3789-3794, 1992. [PubMed: 1371279]
Basani, R. B., Brown, D. L., Vilaire, G., Bennett, J. S., Poncz, M. A leu(117)--trp mutation within the RGD-peptide cross-linking region of beta-3 results in Glanzmann thrombasthenia by preventing alpha-IIb-beta-3 export to the platelet surface. Blood 90: 3082-3088, 1997. [PubMed: 9376589]
Bray, P. F., Barsh, G., Rosa, J.-P., Luo, X. Y., Magenis, E., Shuman, M. A. Physical linkage of the genes for platelet membrane glycoproteins IIb and IIIa. Proc. Nat. Acad. Sci. 85: 8683-8687, 1988. [PubMed: 3186752] [Full Text: https://doi.org/10.1073/pnas.85.22.8683]
Bray, P. F., Rosa, J.-P., Johnston, G. I., Shiu, D. T., Cook, R. G., Lau, C., Kan, Y. W., McEver, R. P., Shuman, M. A. Platelet glycoprotein IIb: chromosomal localization and tissue expression. J. Clin. Invest. 80: 1812-1817, 1987. [PubMed: 3479442] [Full Text: https://doi.org/10.1172/JCI113277]
Bray, P. F., Shuman, M. A. Analysis of the genes for platelet glycoproteins IIb and IIIa (17q21.32) in a normal population and a family with Glanzmann thrombasthenia: identification of two polymorphisms and a rearranged GPIIIa gene. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A177 only, 1989.
Bray, P. F., Shuman, M. A. Identification of an abnormal gene for the GPIIIa subunit of the platelet fibrinogen receptor resulting in Glanzmann's thrombasthenia. Blood 75: 881-888, 1990. [PubMed: 1967954]
Burk, C., Ingram, C., Weiner, M., Rappaport, E. F., Schwartz, E., Poncz, M. A Taq I polymorphism for the human platelet glycoprotein IIIa gene (GP3A). Nucleic Acids Res. 16: 7216 only, 1988. [PubMed: 2900503] [Full Text: https://doi.org/10.1093/nar/16.14.7216]
Chen, F., Coller, B. S., French, D. L. Homozygous mutation of platelet glycoprotein IIIa (beta-3) cys374-to-tyr in a Chinese patient with Glanzmann thrombasthenia. (Abstract) Blood 82: 163a only, 1993.
Chen, Y.-P., Djaffar, I., Pidard, D., Steiner, B., Cieutat, A.-M., Caen, J. P., Rosa, J.-P. Ser-752-to-pro mutation in the cytoplasmic domain of integrin beta-3 subunit and defective activation of platelet integrin alpha-IIb/beta-3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia. Proc. Nat. Acad. Sci. 89: 10169-10173, 1992. [PubMed: 1438206] [Full Text: https://doi.org/10.1073/pnas.89.21.10169]
Faccio, R., Takeshita, S., Zallone, A., Ross, F. P., Teitelbaum, S. L. c-Fms and the alpha-V-beta-3 integrin collaborate during osteoclast differentiation. J. Clin. Invest. 111: 749-758, 2003. [PubMed: 12618529] [Full Text: https://doi.org/10.1172/JCI16924]
Ferrer, M., Tao, J., Iruin, G., Sanchez-Ayuso, M., Gonzalez-Rodriguez, J., Parrilla, R., Gonzalez-Manchon, C. Truncation of glycoprotein (GP) IIIa (delta 616-762) prevents complex formation with GPIIb: novel mutation in exon 11 of GPIIIa associated with thrombasthenia. Blood 92: 4712-4720, 1998. [PubMed: 9845537]
Furihata, K., Nugent, D. J., Bissonette, A., Aster, R. H., Kunicki, T. J. On the association of the platelet-specific alloantigen, Pen(a), with glycoprotein IIIa: evidence for heterogeneity of glycoprotein IIIa. J. Clin. Invest. 80: 1624-1630, 1987. [PubMed: 2445781] [Full Text: https://doi.org/10.1172/JCI113250]
Ghevaert, C., Salsmann, A., Watkins, N. A., Schaffner-Reckinger, E., Rankin, A., Garner, S. F., Stephens, J., Smith, G. A., Debili, N., Vainchenker, W., de Groot, P. G., Huntington, J. A., Laffan, M., Kieffer, N., Ouwehand, W. H. A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIb/beta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia. Blood 111: 3407-3414, 2008. [PubMed: 18065693] [Full Text: https://doi.org/10.1182/blood-2007-09-112615]
Ginsberg, M. H., Lightsey, A., Kunicki, T. J., Kaufmann, A., Marguerie, G., Plow, E. F. Divalent cation regulation of the surface orientation of platelet membrane glycoprotein IIb: correlation with fibrinogen binding function and definition of a novel variant of Glanzmann's thrombasthenia. J. Clin. Invest. 78: 1103-1111, 1986. [PubMed: 2428841] [Full Text: https://doi.org/10.1172/JCI112667]
Goldschmidt-Clermont, P. J., Coleman, L. D., Pham, Y. M., Cooke, G. E., Shear, W. S., Weiss, E. J., Kral, B. G., Moy, T. F., Yook, R. M., Blumenthal, R. S., Becker, D. M., Becker, L. C., Bray, P. F. Higher prevalence of GPIIIa Pl(A2) polymorphism in siblings of patients with premature coronary heart disease. Arch. Path. Lab. Med. 123: 1223-1229, 1999. [PubMed: 10583927] [Full Text: https://doi.org/10.5858/1999-123-1223-HPOGPA]
Goldschmidt-Clermont, P. J., Shear, W. S., Schwartzberg, J., Varga, C. F., Bray, P. F. Clues to the death of an Olympic champion. (Letter) Lancet 347: 1833 only, 1996. [PubMed: 8667943] [Full Text: https://doi.org/10.1016/s0140-6736(96)91652-9]
Gong, H., Shen, B., Flevaris, P., Chow, C., Lam, S. C.-T., Voyno-Yasenetskaya, T. A., Kozasa, T., Du, X. G protein subunit G-alpha-13 binds to integrin alphaIIb-beta-3 and mediates integrin 'outside-in' signaling. Science 327: 340-343, 2010. [PubMed: 20075254] [Full Text: https://doi.org/10.1126/science.1174779]
Gordeeva, E. My Sergei--A Love Story. New York: Warner Books, Inc. 1996.
Gresele, P., Falcinelli, E., Giannini, S., D'Adamo, P., D'Eustacchio, A., Corazzi, T., Mezzasoma, A. M., Di Bari, F., Guglielmini, G., Cecchetti, L., Noris, P., Balduini, C. L., Savoia, A. Dominant inheritance of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families. Haematologica 94: 663-669, 2009. [PubMed: 19336737] [Full Text: https://doi.org/10.3324/haematol.2008.002246]
Hodivala-Dilke, K. M., McHugh, K. P., Tsakiris, D. A., Rayburn, H., Crowley, D., Ullman-Cullere, M., Ross, F. P., Coller, B. S., Teitelbaum, S., Hynes, R. O. Beta-3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J. Clin. Invest. 103: 229-238, 1999. [PubMed: 9916135] [Full Text: https://doi.org/10.1172/JCI5487]
Hynes, R. O. Integrins: a family of cell surface receptors. Cell 48: 549-554, 1987. [PubMed: 3028640] [Full Text: https://doi.org/10.1016/0092-8674(87)90233-9]
Jallu, V., Dusseaux, M., Panzer, S., Torchet, M.-F., Hezard, N., Goudemand, J., de Brevern, A. G., Kaplan, C. Alpha-IIb-beta-3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function. Hum. Mutat. 31: 237-246, 2010. [PubMed: 20020534] [Full Text: https://doi.org/10.1002/humu.21179]
Jayo, A., Conde, I., Lastres, P., Martinez, C., Rivera, J., Vicente, V., Gonzalez-Manchon, C. L718P mutation in the membrane-proximal cytoplasmic tail of beta3 promotes abnormal alphaIIb/beta3 clustering and lipid microdomain coalescence, and associates with a thrombasthenia-like phenotype. Haematologica 95: 1158-1166, 2010. [PubMed: 20081061] [Full Text: https://doi.org/10.3324/haematol.2009.018572]
Jiang, G., Giannone, G., Critchley, D. R., Fukumoto, E., Sheetz, M. P. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424: 334-337, 2003. [PubMed: 12867986] [Full Text: https://doi.org/10.1038/nature01805]
Jin, Y., Dietz, H. C., Montgomery, R. A., Bell, W. R., McIntosh, I., Coller, B., Bray, P. F. Glanzmann thrombasthenia: cooperation between sequence variants in Cis during splice site selection. J. Clin. Invest. 98: 1745-1754, 1996. [PubMed: 8878424] [Full Text: https://doi.org/10.1172/JCI118973]
Kekomaki, R., Dawson, B., McFarland, J., Kunicki, T. J. Localization of human platelet autoantigens to the cysteine-rich region of glycoprotein IIIa. J. Clin. Invest. 88: 847-854, 1991. [PubMed: 1715887] [Full Text: https://doi.org/10.1172/JCI115386]
Kekomaki, R., Jouhikainen, T., Ollikainen, J., Westman, P., Laes, M. A new platelet alloantigen, Tu-a, on glycoprotein-IIIa associated with neonatal alloimmune thrombocytopenia in two families. Brit. J. Haemat. 83: 306-310, 1993. [PubMed: 8457479] [Full Text: https://doi.org/10.1111/j.1365-2141.1993.tb08286.x]
Kim, H. O., Jin, Y., Kickler, T. S., Blakemore, K., Kwon, O. H., Bray, P. F. Gene frequencies of the five major human platelet antigens in African American, white, and Korean populations. Transfusion 35: 863-867, 1995. [PubMed: 7570918] [Full Text: https://doi.org/10.1046/j.1537-2995.1995.351096026369.x]
Kobayashi, Y., Matsui, H., Kanai, A., Tsumura, M., Okada, S., Miki, M., Nakamura, K., Kunishima, S., Inaba, T., Kobayashi, M. Identification of the integrin beta3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis. Brit. J. Haemat. 160: 521-529, 2013. [PubMed: 23253071] [Full Text: https://doi.org/10.1111/bjh.12160]
Kroll, H., Kiefel, V., Santoso, S., Mueller-Eckhardt, C. Sr-a, a private platelet antigen on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia. Blood 76: 2296-2302, 1990. [PubMed: 2257303]
Kuijpers, R. W. A. M., Simsek, S., Faber, N. M., Goldschmeding, R., van Wermerkerken, R. K. V., von dem Borne, A. E. G. K. Single point mutation in human glycoprotein IIIa is associated with a new platelet-specific alloantigen (Mo) involved in neonatal alloimmune thrombocytopenia. Blood 81: 70-76, 1993. [PubMed: 8093349]
Kunicki, T. J., Pidard, D., Cazenave, J.-P., Nurden, A. T., Caen, J. P. Inheritance of the human platelet alloantigen, Pl(A1), in type I Glanzmann's thrombasthenia. J. Clin. Invest. 67: 717-724, 1981. [PubMed: 7193688] [Full Text: https://doi.org/10.1172/JCI110088]
Lanza, F., Kieffer, N., Phillips, D. R., Fitzgerald, L. A. Characterization of the human platelet glycoprotein IIIa gene: comparison with the fibronectin receptor beta-subunit gene. J. Biol. Chem. 265: 18098-18103, 1990. [PubMed: 2145280]
Lanza, F., Stierle, A., Fournier, D., Morales, M., Andre, G., Nurden, A. T., Cazenave, J.-P. A new variant of Glanzmann's thrombasthenia (Strasbourg I): platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa arg214-to-trp mutation. J. Clin. Invest. 89: 1995-2004, 1992. [PubMed: 1602006] [Full Text: https://doi.org/10.1172/JCI115808]
Lefkovits, J., Plow, E. F., Topol, E. J. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. New Eng. J. Med. 332: 1553-1559, 1995. [PubMed: 7739710] [Full Text: https://doi.org/10.1056/NEJM199506083322306]
Letellier, S. J., Hunter, J. B., Aster, R. H. Probable genetic linkage between genes coding for platelet-specific antigens of the Pl(A) and Bak systems. Am. J. Hemat. 29: 139-143, 1988. [PubMed: 3189308] [Full Text: https://doi.org/10.1002/ajh.2830290304]
Li, R., Mitra, N., Gratkowski, H., Vilaire, G., Litvinov, R., Nagasami, C., Weisel, J. W., Lear, J. D., DeGrado, W. F., Bennett, J. S. Activation of integrin alpha-IIb-beta-3 by modulation of transmembrane helix associations. Science 300: 795-798, 2003. [PubMed: 12730600] [Full Text: https://doi.org/10.1126/science.1079441]
Loftus, J. C., O'Toole, T. E., Plow, E. F., Glass, A., Frelinger, A. L., III, Ginsberg, M. H. A beta-3 integrin mutation abolishes ligand binding and alters divalent cation-dependent conformation. Science 249: 915-918, 1990. [PubMed: 2392682] [Full Text: https://doi.org/10.1126/science.2392682]
McDowall, A., Inwald, D., Leitinger, B., Jones, A., Liesner, R., Klein, N., Hogg, N. A novel form of integrin dysfunction involving beta-1, beta-2, and beta-3 integrins. J. Clin. Invest. 111: 51-60, 2003. [PubMed: 12511588] [Full Text: https://doi.org/10.1172/JCI14076]
Newman, P. J., Derbes, R. S., Aster, R. H. The human platelet alloantigens, Pl(A1) and Pl(A2), are associated with a leucine(33)/proline(33) amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J. Clin. Invest. 83: 1778-1781, 1989. [PubMed: 2565345] [Full Text: https://doi.org/10.1172/JCI114082]
Newman, P. J., Seligsohn, U., Lyman, S., Coller, B. S. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc. Nat. Acad. Sci. 88: 3160-3164, 1991. [PubMed: 2014236] [Full Text: https://doi.org/10.1073/pnas.88.8.3160]
Newman, P. J., Seligsohn, U., Lyman, S., Poncz, M., Coller, B. S. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. (Abstract) Clin. Res. 38: 467A only, 1990.
Newman, P. J. Nomenclature of human platelet alloantigens: a problem with the HPA system? Blood 83: 1447-1451, 1994. [PubMed: 8123835]
O'Donnell, C. J., Larson, M. G., Feng, D., Sutherland, P. A., Lindpaintner, K., Myers, R. H., D'Agostino R. A., Levy, D., Tofler, G. H. Genetic and environmental contributions to platelet aggregation: the Framingham Heart Study. Circulation 103: 3051-3056, 2001. [PubMed: 11425767] [Full Text: https://doi.org/10.1161/01.cir.103.25.3051]
Pastinen, T., Perola, M., Niini, P., Terwilliger, J., Salomaa, V., Vartiainen, E., Peltonen, L., Syvanen, A.-C. Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. Hum. Molec. Genet. 7: 1453-1462, 1998. [PubMed: 9700201] [Full Text: https://doi.org/10.1093/hmg/7.9.1453]
Peretz, H., Rosenberg, N., Landau, M., Usher, S., Nelson, E. J. R., Mor-Cohen, R., French, D. L., Mitchell, B. W., Nair, S. C., Chandy, M., Coller, B. S., Srivastava, A., Seligsohn, U. Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alpha-IIb-beta-3 integrin (ITGA2B, ITGB3). Hum. Mutat. 27: 359-369, 2006. [PubMed: 16463284] [Full Text: https://doi.org/10.1002/humu.20304]
Prandini, M. H., Denarier, E., Frachet, P., Uzan, G., Marguerie, G. Isolation of the human platelet glycoprotein IIb gene and characterization of the 5-prime flanking region. Biochem. Biophys. Res. Commun. 156: 595-601, 1988. [PubMed: 2845986] [Full Text: https://doi.org/10.1016/s0006-291x(88)80884-2]
Raymond, T., Gorbunova, E., Gavrilovskaya, I. N., Mackow, E. R. Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent alpha-V-beta-3 integrin conformers. Proc. Nat. Acad. Sci. 102: 1163-1168, 2005. [PubMed: 15657120] [Full Text: https://doi.org/10.1073/pnas.0406743102]
Reynolds, L. E., Conti, F. J., Lucas, M., Grose, R., Robinson, S., Stone, M., Saunders, G., Dickson, C., Hynes, R. O., Lacy-Hulbert, A., Hodivala-Dilke, K. Accelerated re-epithelialization in beta-3-integrin-deficient mice is associated with enhanced TGF-beta-1 signaling. Nature Med. 11: 167-174, 2005. [PubMed: 15654327] [Full Text: https://doi.org/10.1038/nm1165]
Reynolds, L. E., Wyder, L., Lively, J. C., Taverna, D., Robinson, S. D., Huang, X., Sheppard, D., Hynes, R. O., Hodivala-Dilke, K. M. Enhanced pathological angiogenesis in mice lacking beta-3 integrin or beta-3 and beta-5 integrins. Nature Med. 8: 27-34, 2002. [PubMed: 11786903] [Full Text: https://doi.org/10.1038/nm0102-27]
Rosa, J.-P., Bray, P. F., Gayet, O., Johnston, G. I., Cook, R. G., Jackson, K. W., Shuman, M. A., McEver, R. P. Cloning of glycoprotein IIIa cDNA from human erythroleukemia cells and localization of the gene to chromosome 17. Blood 72: 593-600, 1988. [PubMed: 3165296]
Rosenberg, N., Yatuv, R., Orion, Y., Zivelin, A., Dardik, R., Peretz, H., Seligsohn, U. Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta-3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 89: 3654-3662, 1997. [PubMed: 9160670]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Saunders, P. W. G., Durack, B. E., Narang, H. K. Zw(a) antigen distribution on the human platelet: an electron microscope study using a colloidal gold labelled marker. Brit. J. Haemat. 59: 209-219, 1985. [PubMed: 3882135] [Full Text: https://doi.org/10.1111/j.1365-2141.1985.tb02986.x]
Shen, B., Zhao, X., O'Brien, K. A., Stojanovic-Terpo, A., Delaney, M. K., Kim, K., Cho, J., Lam, S. C.-T., Du, X. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature 503: 131-135, 2013. [PubMed: 24162846] [Full Text: https://doi.org/10.1038/nature12613]
Shibata, Y., Miyaji, T., Ichikawa, Y., Matsuda, I. A new platelet antigen system, Yuk(a)/Yuk(b). Vox Sang. 51: 334-336, 1986. [PubMed: 3798869] [Full Text: https://doi.org/10.1111/j.1423-0410.1986.tb01980.x]
Simsek, S., Heyboer, H., de Bruijne-Admiraal, L. G., Goldschmeding, R., Cuijpers, H. T. M., von dem Borne, A. E. G. K. Glanzmann's thrombasthenia caused by homozygosity for a splice defect that leads to deletion of the first coding exon of the glycoprotein IIIa mRNA. Blood 81: 2044-2049, 1993. [PubMed: 8471765]
Sosnoski, D. M., Emanuel, B. S., Hawkins, A. L., vanTuinen, P., Ledbetter, D. H., Nussbaum, R. L., Kaos, F.-T., Schwartz, E., Phillips, D., Bennett, J. S., Fitzgerald, L. A., Poncz, M. Chromosomal localization of the genes for the vitronectin and fibronectin receptors alpha-subunits and for platelet glycoproteins IIb and IIIa. J. Clin. Invest. 81: 1993-1998, 1988. [PubMed: 2454952] [Full Text: https://doi.org/10.1172/JCI113548]
Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M., Cheresh, D. A. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell. Biol. 155: 459-470, 2001. [PubMed: 11684710] [Full Text: https://doi.org/10.1083/jcb.200106070]
Takagi, J., Petre, B. M., Walz, T., Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110: 599-611, 2002. [PubMed: 12230977] [Full Text: https://doi.org/10.1016/s0092-8674(02)00935-2]
Thornton, M. A., Poncz, M., Korostishevsky, M., Yakobson, E., Usher, S., Seligsohn, U., Peretz, H. The human platelet alpha-IIb gene is not closely linked to its integrin partner beta-3. Blood 94: 2039-2047, 1999. [PubMed: 10477733]
Tofteng, C. L., Bach-Mortensen, P., Bojesen, S. E., Tybjaerg-Hansen, A., Hyldstrup, L., Nordestgaard, B. G. Integrin beta-3 leu33-to-pro polymorphism and risk of hip fracture: 25 years follow-up of 9233 adults from the general population. Pharmacogenet. Genomics 17: 85-91, 2007. [PubMed: 17264806] [Full Text: https://doi.org/10.1097/01.fpc.0000236327.80809.f8]
Undas, A., Brummel, K., Musial, J., Mann, K. G., Szczeklik, A. Pl(A2) polymorphism of beta-3 integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation 104: 2666-2672, 2001. [PubMed: 11723016] [Full Text: https://doi.org/10.1161/hc4701.099787]
Van Cong, N., Uzan, G., Gross, M. S., de Tand, M. F., Frachet, P., Boucheix, C., Marguerie, G., Frezal, J. Assignment of GP3A gene to chromosome 17 (somatic cell hybrid analysis), region q21.1-q21.3 (in situ hybridization). (Abstract) Cytogenet. Cell Genet. 51: 1096-1097, 1989.
von dem Borne, A. E. G., Decary, F. Nomenclature of platelet specific antigens. Hum. Immun. 29: 1-2, 1990. [PubMed: 2211186] [Full Text: https://doi.org/10.1016/0198-8859(90)90063-u]
Wang, R., Furihata, K., McFarland, J. G., Friedman, K., Aster, R. H., Newman, P. J. An amino acid polymorphism within the RGD binding domain of platelet membrane glycoprotein IIIa is responsible for the formation of the Pen(a)/Pen(b) alloantigen system. J. Clin. Invest. 90: 2038-2043, 1992. [PubMed: 1430225] [Full Text: https://doi.org/10.1172/JCI116084]
Wang, R., McFarland, J. G., Kekomaki, R., Newman, P. J. Amino acid 489 is encoded by a mutational 'hot spot' on the beta-3 integrin chain: the CA/TU human platelet alloantigen system. Blood 82: 3386-3391, 1993. [PubMed: 7694683]
Wang, R., Shattil, S. J., Ambruso, D. R., Newman, P. J. Truncation of the cytoplasmic domain of beta-3 in a variant form of Glanzmann thrombasthenia abrogates signaling through the integrin alpha(IIIb)-beta(3) complex. J. Clin. Invest. 100: 2393-2403, 1997. [PubMed: 9351872] [Full Text: https://doi.org/10.1172/JCI119780]
Wang, X., Huang, D. Y., Huong, S.-M., Huang, E.-S. Integrin alpha-v-beta-3 is a coreceptor for human cytomegalovirus. Nature Med. 11: 515-521, 2005. [PubMed: 15834425] [Full Text: https://doi.org/10.1038/nm1236]
Wang, X., Huong, S.-M., Chiu, M. L., Raab-Traub, N., Huang, E.-S. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424: 456-461, 2003. [PubMed: 12879076] [Full Text: https://doi.org/10.1038/nature01818]
Weiss, E. J., Bray, P. F., Tayback, M., Schulman, S. P., Kickler, T. S., Becker, L. C., Weiss, J. L., Gerstenblith, G., Goldschmidt-Clermont, P. J. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. New Eng. J. Med. 334: 1090-1094, 1996. [PubMed: 8598867] [Full Text: https://doi.org/10.1056/NEJM199604253341703]
Weiss, E. J., Goldschmidt-Clermont, P. J., Grigoryev, D., Yin, Y., Kickler, T. S., Bray, P. F. A monoclonal antibody (SZ21) specific for platelet GPIIIa distinguishes PlA1 from PlA2. Tissue Antigens 46: 374-381, 1995. [PubMed: 8838346] [Full Text: https://doi.org/10.1111/j.1399-0039.1995.tb03129.x]
Weiss, L. A., Abney, M., Cook, E. H., Jr., Ober, C. Sex-specific genetic architecture of whole blood serotonin levels. Am. J. Hum. Genet. 76: 33-41, 2005. [PubMed: 15526234] [Full Text: https://doi.org/10.1086/426697]
Weiss, L. A., Ober, C., Cook, E. H., Jr. ITGB3 shows genetic and expression interaction with SLC6A4. Hum. Genet. 120: 93-100, 2006. [PubMed: 16721604] [Full Text: https://doi.org/10.1007/s00439-006-0196-z]
Weiss, L. A., Veenstra-VanderWeele, J., Newman, D. L., Kim, S.-J., Dytch, H., McPeek, M. S., Cheng, S., Ober, C., Cook, E. H., Jr., Abney, M. Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin. Europ. J. Hum. Genet. 12: 949-954, 2004. [PubMed: 15292919] [Full Text: https://doi.org/10.1038/sj.ejhg.5201239]
West, K. A., Anderson, D. R., McAlister, V. C., Hewlett, T. J. C., Belitsky, P., Smith, J. W., Kelton, J. G. Alloimmune thrombocytopenia after organ transplantation. New Eng. J. Med. 341: 1504-1507, 1999. [PubMed: 10559451] [Full Text: https://doi.org/10.1056/NEJM199911113412004]
Xiao, T., Takagi, J., Coller, B. S., Wang, J.-H., Springer, T. A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432: 59-67, 2004. [PubMed: 15378069] [Full Text: https://doi.org/10.1038/nature02976]
Xiong, J.-P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D. L., Joachimiak, A., Goodman, S. L., Arnaout, M. A. Crystal structure of the extracellular segment of integrin alpha-V-beta-3. Science 294: 339-345, 2001. [PubMed: 11546839] [Full Text: https://doi.org/10.1126/science.1064535]
Xiong, J.-P., Stehle, T., Zhang, R., Joachimiak, A., Frech, M., Goodman, S. L., Arnaout, M. A. Crystal structure of the extracellular segment of integrin alpha-V-beta-3 in complex with an Arg-Gly-Asp ligand. Science 296: 151-155, 2002. [PubMed: 11884718] [Full Text: https://doi.org/10.1126/science.1069040]
Zimrin, A. B., Eisman, R., Vilaire, G., Schwartz, E., Bennett, J. S., Poncz, M. Structure of platelet glycoprotein IIIa: a common subunit for two different membrane receptors. J. Clin. Invest. 81: 1470-1475, 1988. [PubMed: 2452834] [Full Text: https://doi.org/10.1172/JCI113478]