Alternative titles; symbols
ORPHA: 140957; DO: 0060691; MONDO: 0008552;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | Bleeding disorder, platelet-type, 16, autosomal dominant | 187800 | Autosomal dominant | 3 | ITGA2B | 607759 |
A number sign (#) is used with this entry because platelet-type bleeding disorder-16 (BDPLT16) is caused by heterozygous mutation in the ITGA2B gene (607759), which encodes platelet glycoprotein alpha-IIb, on chromosome 17q21.31.
Biallelic mutation in the ITGA2B gene causes Glanzmann thrombasthenia-1 (GT1; 273800).
Platelet-type bleeding disorder-16 (BDPLT16) 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 BDPLT, see 231200.
Genetic Heterogeneity of Glanzmann Thrombasthenia-like with Macrothromocytopenia
See BDPLT24 (619271), caused by mutation in the ITGB3 gene (173470) on chromosome 17q21.32. Together the ITGB2B and ITBG3 genes form an integrin, known as platelet glycoprotein GPIIb/III, that is expressed on platelets.
Gross et al. (1960) reported a family in which affected members over 3 generations had petechiae, bleeding from mucous membranes, prolonged bleeding after injury, and severe anemia. Studies revealed prolonged bleeding time, abnormal capillary fragility, and a normal or an increased number of platelets, with giant platelets. Alteration in the concentration of several platelet enzymes was found.
Hardisty et al. (1992) reported a young Italian man with a lifelong history of bleeding from gums and mucocutaneous tissues. Laboratory studies showed modest thrombocytopenia, platelet anisocytosis, and large platelets. Platelet aggregation was decreased, but clot retraction was normal. His platelets had decreased levels of the GPIIb/IIIa complex compared to controls (40-50% by crossed immunoelectrophoresis), and further decreased surface expression (12-20% using monocloncal antibodies). Surface expression of GPIIb/IIIa increased upon platelet stimulation, suggesting a substantial amount of these proteins in the internal platelet store. His father also showed platelet anisocytosis and large platelets. This family was also studied by Peyruchaud et al. (1998) and Nurden et al. (2011).
Kunishima et al. (2011) reported 11 patients from 4 unrelated Japanese families with congenital macrothrombocytopenia. Bleeding tendency was mild or absent. Platelet aggregation was decreased, but bleeding time was normal, and platelet spreading on fibrinogen was partially impaired. Patient platelets showed decreased surface expression of GPIIb/IIIa (50-70% of controls).
Of 13 families with an apparent diagnosis of Glanzmann thrombasthenia studied by Caen et al. (1966), one seemed to have dominant inheritance with probable transmission through 4 generations with male-to-male transmission.
The transmission pattern of Glanzmann thrombasthenia-like with macrothrombocytopenia in the family reported by Kunishima et al. (2011) was consistent with autosomal dominant inheritance.
In an Italian man with macrothrombocytopenia reported by Hardisty et al. (1992), Peyruchaud et al. (1998) identified a heterozygous mutation in the ITGA2B gene (R995Q; 607759.0017). In vitro functional expression studies in CHO cells indicated that the R995Q mutation would give rise to an integrin complex that is more easily activatable compared to wildtype.
In 11 patients from 4 Japanese families with BDPLT16, Kunishima et al. (2011) identified a heterozygous mutation in the ITGA2B gene (R995W; 607759.0018). The disease haplotype was unique in each family, indicating independent occurrence. In vitro studies indicated that mutant protein assumed a constitutive, activated conformation, but did not induce platelet activation. Transfection of the mutation into CHO cells and mouse liver-derived megakaryocytes resulted in abnormal membrane ruffling and cytoplasmic protrusions, as well as defect proplatelet formation. The findings were reminiscent of the activating D723H mutation in ITGB3 (173470.0018), and Kunishima et al. (2011) concluded that activating mutations in ITGA2B and ITGB3 are responsible for a subset of congenital macrothrombocytopenias.
In von Willebrand disease (193400), factor VIII is low and the platelets show faulty adhesion to glass. In hereditary thrombopathy, availability of platelet factor-3 is reduced and platelets do not aggregate on exposure to collagen. Crowell and Eisner (1972) described a family with a combination of these abnormalities in affected persons in several successive generations without male-to-male transmission.
Caen, J. P., Castaldi, P. A., Leclerc, J. C., Inceman, S., Larrieu, M. J., Probst, M., Bernard, J. Congenital bleeding disorders with long bleeding time and normal platelet count. I. Glanzmann's thrombasthenia (report of fifteen patients). Am. J. Med. 41: 4-26, 1966.
Crowell, E. B., Jr., Eisner, E. V. Familial association of thrombopathia and antihemophilic factor (AHF, factor VIII) deficiency. Blood 40: 227-233, 1972. [PubMed: 4537881]
Gross, R., Gerok, W., Lohr, G. W., Vogell, W., Walker, H. D., Theopold, W. Ueber die Natur der Thrombasthenie: Thrombopathie Glanzmann Naegeli. Klin. Wschr. 38: 193-206, 1960. [PubMed: 13829663]
Hardisty, R., Pidard, D., Cox, A., Nokes, T., Legrand, C., Bouillot, C., Pannocchia, A., Heilmann, E., Hourdille, P., Bellucci, S., Nurden, A. A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder. Blood 80: 696-708, 1992. [PubMed: 1638023]
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]
Peyruchaud, O., Nurden, A. T., Milet, S., Macchi, L., Pannochia, A., Bray, P. F., Kieffer, N., Bourre, F. R to Q amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin alphaIIb subunit in a patient with a Glanzmann's thrombasthenia-like syndrome. Blood 92: 4178-4187, 1998. [PubMed: 9834222]