Alternative titles; symbols
ORPHA: 849; MONDO: 0031009;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.32 | Glanzmann thrombasthenia 2 | 619267 | Autosomal recessive | 3 | ITGB3 | 173470 |
A number sign (#) is used with this entry because Glanzmann thrombasthenia-2 (GT2) is caused by homozygous or compound heterozygous mutation in the ITGB3 gene (173470), which encodes platelet glycoprotein IIIa, on chromosome 17q21.
Heterozygous mutation in the ITGB3 gene causes Glanzmann thrombasthenia-like with macrothrombocytopenia-2 (BDPLT24; 619271).
Glanzmann thrombasthenia-2 (GT2) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb (607759)/IIIa platelet surface fibrinogen receptor complex resulting from mutations in the GPIIIa gene (Rosenberg et al., 1997).
For a general phenotypic description and a discussion of genetic heterogeneity of Glanzmann thrombasthenia, see 273800.
For a discussion of genetic heterogeneity of platelet-type bleeding disorder (BDPLT), see 231200.
Glanzmann thrombasthenia (GT) is manifest soon after birth with episodic mucocutaneous bleeding and unprovoked bruising. Epistaxis frequently occurs and, in women, copious menstrual hemorrhage. Intracranial bleeding may also occur. Bleeding time is prolonged, with normal platelet count, normal platelet morphology, and normal coagulation times. Platelets fail to aggregate, either spontaneously or in response to agonists, such as ADP, thrombin, or epinephrine, although there may be a transient response to ristocetin (Ferrer et al., 1998; Poncz et al., 1994).
The transmission pattern of Glanzmann thrombasthenia-2 in the families reported by Newman et al. (1991) was consistent with autosomal recessive inheritance.
Newman et al. (1991) demonstrated that the form of Glanzmann thrombasthenia frequent in Iraqi Jews is due to a truncated GPIIIa as a result of an 11-bp deletion within the GP3A gene (173470.0014), whereas the form of the disease frequent in Arabs in Israel is due to a 13-bp deletion in the GP2B gene (607759.0002).
In a patient with Glanzmann thrombasthenia, Bajt et al. (1992) identified a mutation in the ITGB3 gene (173470.0001). The patient's platelets failed to aggregate in response to stimuli.
Peretz et al. (2006) investigated the molecular basis of Glanzmann thrombasthenia in 40 families from southern India. Of 23 identified mutations, 13 in the ITGA2B gene and 10 in the ITGB3 gene, 20 were novel. A founder effect was observed for 2 mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the ITGB3 gene, and for 10 of 11 frameshift or nonsense mutations in ITGA2B or ITGB3.
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 (see, e.g., 173470.0016-173470.0017) gene 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.
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]
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]
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]
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]
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]
Poncz, M., Rifat, S., Coller, B. S., Newman, P. J., Shattil, S. J., Parrella, T., Fortina, P., Bennett, J. S. Glanzmann thrombasthenia secondary to a gly273-to-asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J. Clin. Invest. 93: 172-179, 1994. [PubMed: 8282784] [Full Text: https://doi.org/10.1172/JCI116942]
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]