Alternative titles; symbols
HGNC Approved Gene Symbol: GP1BB
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,723,539-19,724,771 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
22q11.21 | Bernard-Soulier syndrome, type B | 231200 | Autosomal recessive | 3 |
Giant platelet disorder, isolated | 231200 | Autosomal recessive | 3 |
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).
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.
Kelly et al. (1994) reported that the coding region of the GP1BB gene is contained within 1 exon, similar to GP1BA, GP9, and GP5.
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.
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.
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. 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.
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).
For discussion of the ala108-to-pro (A108P) mutation in the GP1BB gene that was found in compound heterozygous state in patients with a giant platelet disorder that was not accompanied by thrombocytopenia or leukocyte inclusions (see 231200) by Kunishima et al. (1997), see 138720.0001.
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.
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.
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. [PubMed: 7633430] [Full Text: https://doi.org/10.1093/hmg/4.4.763]
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. [PubMed: 15213102] [Full Text: https://doi.org/10.1182/blood-2004-03-1127]
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. [PubMed: 8200976] [Full Text: https://doi.org/10.1172/JCI117249]
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. [PubMed: 9116284]
Lopez, J. A., Andrews, R. K., Afshar-Kharghan, V., Berndt, M. C. Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998. [PubMed: 9616133]
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. [PubMed: 3353370] [Full Text: https://doi.org/10.1073/pnas.85.7.2135]
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. [PubMed: 8703016] [Full Text: https://doi.org/10.1074/jbc.271.36.22076]
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. [PubMed: 10887115]
Roth, G. J. The wanderings of a platelet gene: what is 'neo' Ib-beta telling us? (Editorial) J. Clin. Invest. 93: 2301-2302, 1994. [PubMed: 8200960] [Full Text: https://doi.org/10.1172/JCI117231]
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. [PubMed: 8021244]
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. [PubMed: 9022087] [Full Text: https://doi.org/10.1172/JCI119188]