TY - JOUR AU - Paolo Gresele, AU - Emanuela Falcinelli, AU - Silvia Giannini, AU - Pio D’Adamo, AU - Angela D’Eustacchio, AU - Teresa Corazzi, AU - Anna Maria Mezzasoma, AU - Filomena Di Bari, AU - Giuseppe Guglielmini, AU - Luca Cecchetti, AU - Patrizia Noris, AU - Carlo L. Balduini, AU - Anna Savoia, PY - 2009/04/30 Y2 - 2024/03/29 TI - Dominant inheritance of a novel integrin β3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families JF - Haematologica JA - haematol VL - 94 IS - 5 SE - Articles DO - 10.3324/haematol.2008.002246 UR - https://haematologica.org/article/view/5244 SP - 663-669 AB - Background Defects of integrin αIIbβ3 are typical of Glanzmann’s thrombasthenia, an inherited autosomal recessive bleeding disorder characterized by the failure of platelets to aggregate in response to all physiological agonists, but with no abnormalities in the number or size of platelets. Although large heterogeneity has been described for Glanzmann’s thrombasthenia, no family has so far been described as having an autosomal dominant form of this disease.Design and Methods We describe two Italian families with moderate thrombocytopenia with large platelets, defective platelet function and moderate/severe mucocutaneous bleeding, transmitted as an autosomal dominant trait and associated with a novel integrin β3-gene (ITGB3) mutation.Results The characteristics of our families are moderate macrothrombocytopenia and defective platelet function associated with a mild reduction of surface αIb β3, impaired platelet aggregation to physiological agonists but not to ristocetin, normal clot retraction, reduced fibrinogen binding and expression of activated αIIbβ3 upon stimulation, normal platelet adhesion to immobilized fibrinogen but reduced platelet spreading and tyrosine phosphorylation, indicating defective αIIbβ3-mediated outside-in signaling. Molecular analysis revealed a novel mutation of ITGB3 that determines an in-frame deletion producing the loss of amino acids 647–686 of the βTD ectodomain of integrin β3. Haplotype analysis indicated that the two families inherited the mutation from a common ancestral chromosome.Conclusions This novel autosomal dominant macrothrombocytopenia associated with platelet dysfunction raises interesting questions about the role of integrin β3, and its βTD domain, in platelet formation and function. ER -