Alternative titles; symbols
ORPHA: 140957; MONDO: 0030996;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.32 | Bleeding disorder, platelet-type, 24, autosomal dominant | 619271 | Autosomal dominant | 3 | ITGB3 | 173470 |
A number sign (#) is used with this entry because platelet-type bleeding disorder-24 (BDPLT24) is caused by heterozygous mutation in the ITGB3 gene (173470), which encodes platelet glycoprotein alpha-III, on chromosome 17q21.32.
Biallelic mutation in the ITGB3 gene causes Glanzmann thrombasthenia-2 (GT2; 619267).
Platelet-type bleeding disorder-24 (BDPLT24) is an autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities (summary by Kunishima et al., 2011 and Nurden et al., 2011).
For a discussion of genetic heterogeneity of Glanzmann thrombasthenia-like with macrothrombocytopenia, see 187800.
For a discussion of genetic heterogeneity of platelet-type bleeding disorder (BDPLT), see 231200.
Ghevaert et al. (2008) reported a family in which 5 individuals had macrothrombocytopenia. GPIIb (607759)/IIIa expression on platelets was normal, and none of the affected individuals had bleeding abnormalities; the defect in the proband was an incidental finding.
Gresele et al. (2009) reported 2 unrelated Italian families with autosomal dominant BDPLT24. 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 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. n which 10 individuals had mild bleeding tendencies, such as nasal bleeding and purpura, associated with macrothrombocytopenia and platelet anisocytosis. Laboratory studies showed decreased platelet aggregation by physiologic agonists. 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 could not be fully activated in the presence of such signals.
Jayo et al. (2010) reported a Spanish woman with a lifelong history of mucocutaneous bleeding tendency associated with moderate thrombocytopenia and platelet anisocytosis. Functional studies showed decreased platelet agglutination to physiologic agonists and impaired spreading on fibrinogen. There was no family history of a similar disorder.
Kobayashi et al. (2013) reported a 4-generation Japanese kindred in which 10 individuals had mild bleeding tendencies, such as nasal bleeding and purpura, associated with macrothrombocytopenia and platelet anisocytosis. Laboratory studies showed decreased platelet aggregation by physiologic agonists. 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 could not be fully activated in the presence of such signals.
The transmission pattern of Glanzmann thrombasthenia-like with macrothrombocytopenia in the families reported by Ghevaert et al. (2008), Gresele et al. (2009), and Kobayashi et al. (2013) was consistent with autosomal dominant inheritance.
In 5 members of a family with autosomal dominant BDPLT24 manifest as macrothrombocytopenia, 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, causing disruption of a conserved salt bridge between D723 in ITGB3 and residue R995 in the ITGA2B gene (607759). In vitro functional expression assays showed that the mutant protein was constitutively active. Cells transfected with the mutation exhibited spontaneous and specific increased binding of the antibody PAC-1, increased adhesion to von Willebrand factor (VWF) in static conditions, and increased binding to fibrinogen under shear stress compared to wildtype, all consistent with a gain of function. 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 incorrect sizing of platelets during formation, resulting in thrombocytopenia due to increased platelet turnover.
In affected members of 2 unrelated Italian families with autosomal dominant BDPLT24, Gresele et al. (2009) identified a heterozygous splice site mutation in the ITGB3 gene (173470.0019). Haplotype analysis suggested a founder effect. In vitro studies suggested defective GPIIb/IIIa outside-in signaling. 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 a bleeding disorder, thrombocytopenia, platelet anisocytosis, and reduced platelet aggregation, Jayo et al. (2010) identified a de novo heterozygous mutation in the ITGB3 gene (L718P; 173470.0020).
Kobayashi et al. (2013) identified a heterozygous L718P mutation in the ITGB3 gene in affected members of a 4-generation Japanese family with BDPLT24. 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.
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]
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]
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]
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]
Kunishima, S., Kashiwagi, H., Otsu, M., Takayama, N., Eto, K., Onodera, M., Miyajima, Y., Takamatsu, Y., Suzumiya, J., Matsubara, K., Tomiyama, Y., Saito, H. Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIb/beta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia. Blood 117: 5479-5484, 2011. [PubMed: 21454453] [Full Text: https://doi.org/10.1182/blood-2010-12-323691]
Nurden, A. T., Pillois, X., Fiore, M., Heilig, R., Nurden, P. Glanzmann thrombasthenia-like syndromes associated with macrothrombocytopenias and mutations in the genes encoding the alphaIIb/beta3 integrin. Semin. Thromb. Hemost. 37: 698-706, 2011. [PubMed: 22102273] [Full Text: https://doi.org/10.1055/s-0031-1291380]