Alternative titles; symbols
HGNC Approved Gene Symbol: GP9
Cytogenetic location: 3q21.3 Genomic coordinates (GRCh38): 3:129,054,845-129,062,406 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3 | Bernard-Soulier syndrome, type C | 231200 | Autosomal recessive | 3 |
Platelet glycoprotein IX (GP9) is a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib (GP Ib), a platelet surface membrane glycoprotein complex 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 (GP1BB; 138720), that are linked by disulfide bonds. The complete receptor complex includes noncovalent association of the alpha and beta subunits with GP9 and platelet glycoprotein V (GP5; 173511) (review by Lopez et al., 1998).
Using antibody screening of a human erythroleukemia cell (HEL) cDNA library, Hickey et al. (1989, 1990) cloned a cDNA that encodes GP IX and determined its nucleotide sequence. The predicted 165-amino acid protein has a molecular mass of about 17 kD and includes a 24-amino acid leucine-rich glycoprotein (LRG) segment. Leucine-rich segments are also found in the GP Ib alpha chain, beta chain, and GP5. Hydropathy analysis indicated that GP IX is a transmembrane protein with an extracellular region of 134 residues, and an intracytoplasmic region of 6 residues. Hickey et al. (1989) suggested that the GP9 protein may provide for membrane insertion and orientation of the larger component of the complex, GP Ib.
By hybridization of GP9 cDNA to sorted human chromosomes, Hickey et al. (1990) localized the GP9 gene to chromosome 3. By fluorescence in situ hybridization, Yagi et al. (1995) mapped the GP9 gene to 3q21.
In a family with a variant of Bernard-Soulier syndrome (BSS; 231200), characterized by a pronounced imbalance in the expression of GP IX in relation to the GP Ib-alpha, GP Ib-beta, and GP V chains of the platelet membrane glycoprotein complex, Clemetson et al. (1994) identified homozygosity for a mutation in the GP9 gene (173515.0001).
Meehan et al. (2017) reported that knockout of Gp9 in mice caused thrombocytopenia with increased platelet volume.
In a rare case of variant Bernard-Soulier syndrome (231200) showing a pronounced imbalance in the expression of GP IX in relation to the GP Ib-alpha, GP Ib-beta, and GP V chains of the platelet membrane glycoprotein complex, Clemetson et al. (1994) identified homozygosity for an A-to-G transition resulting in an asn45-to-ser (N45S) substitution within the leucine-rich domain of the glycoprotein IX molecule. No mutations were found in GP Ib-alpha. The mutation created a new cleavage site for the restriction enzyme Fnu4HI. The substitution did not affect glycosylation at the neighboring asn44. The patient, a 23-year-old man, had a lifelong bleeding problem, including epistaxis. He was thrombocytopenic since childhood, with a platelet count of 30,000 to 60,000/microliter, and had a prolonged bleeding time. Peripheral blood smears showed giant platelets.
Sachs et al. (2003) studied blood samples from 4 unrelated German patients with Bernard-Soulier syndrome living in different federal states. All were found to have the N45S mutation. Sachs et al. (2003) commented that the N45S mutation had been identified in British, Austrian, Swedish, Belgian, and multiple Finnish patients, and suggested that it may be an ancient mutation shared by northern and central European populations. They also commented that Bernard-Soulier syndrome is often misdiagnosed as immune thrombocytopenia; this was the case in 3 of the 4 patients they reported.
Wright et al. (1993) reported a family with classic Bernard-Soulier syndrome (231200) in which lesions of the GP1BA gene were excluded. On the other hand, they found compound heterozygosity for 2 different mutations of the GP9 gene: an A-to-G transition in codon 21, resulting in conversion of an aspartic acid to glycine (D21G), and an A-to-G transition in codon 45, converting an asparagine residue to serine (173515.0001). The alterations occurred in conserved residues in or flanking the GP IX leucine-rich glycoprotein motif. Both mutations created new recognition sites for the restriction enzyme Fnu4HI (isoschizomer, BsoFI). In screening 120 alleles in 60 normal subjects for Fnu4HI restriction, Wright et al. (1993) did not detect the mutations in any subjects other than direct relatives of the affected sibs.
Noris et al. (1997) investigated the molecular basis of a case of Bernard-Soulier syndrome (231200) with deficient expression of GP IX, as detected by immunofluorescence studies. Nucleotide sequence analysis of the coding region showed a homozygous point mutation predicting a phenylalanine-to-serine substitution at position 55 (F55S) of the mature GP IX polypeptide within its unique leucine-rich repeat. By allele-specific oligonucleotide hybridization, they confirmed the homozygosity of the patient as well as the heterozygous state of 3 of his children studied. The parents of the patient, who were first cousins, were not available for study.
In a family with Bernard-Soulier syndrome (231200), Noris et al. (1998) identified a homozygous 1811T-C transition in the GP9 gene, resulting in a leu40-to-pro substitution (L40P), in a brother and sister affected by severe bleeding diathesis. Members of the family with mild bleeding diathesis and/or giant platelets in peripheral blood were heterozygous for the mutation, whereas the healthy members were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the 2 severely affected patients.
In a Pakistani boy with Bernard-Soulier syndrome (231200), Rivera et al. (2001) identified a homozygous 1717T-C transition in the GP9 gene, resulting in a cys8-to-arg (C8R) missense mutation. The 2.5-year-old patient was evaluated for a lifelong history of easy bruising, prolonged bleeding from lacerations, and low platelet counts, first noted at the age of 2 months. The parents were consanguineous.
In a man whose case history had been published by Bernard et al. (1957) and who represented the second case of Bernard-Soulier syndrome (231200), Lanza et al. (2002) found a homozygous T-to-C transition at position 1667 of the glycoprotein IX (GP IX) gene resulting in a leu7-to-pro (L7P) mutation in the signal peptide of the protein. This mutation was said to have been the only known example, up to that time, of a leader sequence defect in Bernard-Soulier syndrome. The mutation presumably led to an abnormal conformation and, hence, incorrect insertion of GP IX into the endoplasmic reticulum and/or to defective signal peptide cleavage, both of which are required for correct transport to the cell membrane.
Bernard, J., Caen, J., Maroteaux, P. La dystrophie thrombocytaire hemorragipare congenitale. Rev. Hemat. 12: 222-249, 1957. [PubMed: 13442197]
Clemetson, J. M., Kyrle, P. A., Brenner, B., Clemetson, K. J. Variant Bernard-Soulier syndrome associated with a homozygous mutation in the leucine-rich domain of glycoprotein IX. Blood 84: 1124-1131, 1994. [PubMed: 8049428]
Hickey, M. J., Deaven, L. L., Roth, G. J. Human platelet glycoprotein IX: characterization of cDNA and localization of the gene to chromosome 3. FEBS Lett. 274: 189-192, 1990. [PubMed: 2253772] [Full Text: https://doi.org/10.1016/0014-5793(90)81361-q]
Hickey, M. J., Williams, S. A., Roth, G. J. Human platelet glycoprotein IX: an adhesive prototype of leucine-rich glycoproteins with flank-center-flank structures. Proc. Nat. Acad. Sci. 86: 6773-6777, 1989. [PubMed: 2771955] [Full Text: https://doi.org/10.1073/pnas.86.17.6773]
Lanza, F., de la Salle, C., Baas, M.-J., Schwartz, A., Boval, B., Cazenave, J.-P., Caen, J. P. A leu7-to-pro mutation in the signal peptide of platelet glycoprotein (GP)IX in a case of Bernard-Soulier syndrome abolishes surface expression of the GPIb-V-IX complex. Brit. J. Haemat. 118: 260-266, 2002. [PubMed: 12100158] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03544.x]
Lopez, J. A., Andrews, R. K., Afshar-Kharghan, V., Berndt, M. C. Bernard-Soulier syndrome. Blood 91: 4397-4418, 1998. [PubMed: 9616133]
Meehan, T. F., Conte, N., West, D. B., Jacobsen, J. O., Mason, J., Warren, J., Chen, C.-K., Tudose, I., Relac, M., Matthews, P., Karp, N., Santos, L., and 52 others. Disease model discovery from 3,328 gene knockouts by the International Mouse Phenotyping Consortium. Nature Genet. 49: 1231-1238, 2017. [PubMed: 28650483] [Full Text: https://doi.org/10.1038/ng.3901]
Noris, P., Arbustini, E., Spedini, P., Belletti, S., Balduini, C. L. A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. Brit. J. Haemat. 103: 1004-1013, 1998. [PubMed: 9886312] [Full Text: https://doi.org/10.1046/j.1365-2141.1998.01100.x]
Noris, P., Simsek, S., Stibbe, J., von dem Borne, A. E. G. K. A phenylalanine-55 to serine amino-acid substitution in the human glycoprotein IX leucine-rich repeat is associated with Bernard-Soulier syndrome. Brit. J. Haemat. 97: 312-320, 1997. [PubMed: 9163595] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.582706.x]
Rivera, C. E., Villagra, J., Riordan, M., Williams, S., Lindstrom, K. J., Rick, M. E. Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with Bernard-Soulier syndrome. Brit. J. Haemat. 112: 105-108, 2001. [PubMed: 11167791] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02529.x]
Sachs, U. J. H., Kroll, H., Matzdorff, A. C., Berghofer, H., Lopez, J. A., Santoso, S. Bernard-Soulier syndrome due to the homozygous asn-45ser mutation in GPIX: an unexpected, frequent finding in Germany. Brit. J. Haemat. 123: 127-131, 2003. [PubMed: 14510954] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04554.x]
Wright, S. D., Michaelides, K., Johnson, D. J. D., West, N. C., Tuddenham, E. G. D. Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome. Blood 81: 2339-2347, 1993. [PubMed: 8481514]
Yagi, M., Edelhoff, S., Disteche, C. M., Roth, G. J. Human platelet glycoproteins V and IX: mapping of two leucine-rich glycoprotein genes to chromosome 3 and analysis of structures. Biochemistry 34: 16132-16137, 1995. [PubMed: 8519770] [Full Text: https://doi.org/10.1021/bi00049a028]