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.

Bernard Soulier Syndrome, Type B

In a patient reported by Budarf et al. (1995) with Bernard-Soulier syndrome, type B (see BSS, 231200) and velocardiofacial syndrome (192430) due to a heterozygous deletion in 22q11.2, Ludlow et al. (1996) identified a heterozygous mutation in the upstream promoter of the GP1BB gene (138720.0004). Thus, the patient had autosomal recessive BSS resulting from deletion of 1 copy of the GP1BB gene and mutation in the other copy. The patient reported by Budarf et al. (1995) 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. Budarf et al. (1995) had initially reasoned that 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 a 57-year-old Irish man, born of consanguineous parents, with Bernard-Soulier syndrome, type B, Moran et al. (2000) identified a homozygous nonsense mutation in the GP1BB gene (Y21X; 138720.0003). 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.

Familial Macrothrombocytopenia, Bernard-Soulier Type

In 2 Japanese sisters with the Bernard-Soulier type of familial macrothrombocytopenia (see 231200), Kunishima et al. (1997) identified compound heterozygous missense mutations in the GP1BB gene (Y88C, 138720.0001 and A108P, 138720.0002) that impaired the GP Ib alpha/beta disulfide linkage. 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.

Fetomaternal Alloimmune Thrombocytopenia

In a review of human platelet antigens (HPA), Curtis and McFarland (2014) stated that a G15E missense variant in the GP1BB gene had been found to cause fetomaternal alloimmune thrombocytopenia (FMAIT; see 621264). The GP1BB antigen was termed HPA-12bw.

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.