ClinVar

In affected members of 2 unrelated Italian families with autosomal dominant platelet-type bleeding disorder-24 (BDPLT24; 619267), Gresele et al. (2009) identified a heterozygous G-to-C transversion in intron 13 of the ITGB3 gene (c.2134+1G-C), resulting in an in-frame 120-bp deletion in exon 13, with loss of 40 residues from the extracellular domain (asp647_glu686del). The mutation segregated with the phenotype in the family and was not found in 150 unrelated controls. Haplotype analysis suggested a founder effect. 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 reduced 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. Spontaneous aggregation was absent. 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.