Dominant inheritance of a novel integrin {beta}3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families

1 Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia 2 Medical Genetics, Department of Reproductive and Developmental Science, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, Trieste 3 Telethon Institute of Genetics and Medicine, Naples 4 Department of Internal Medicine, University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Matteo Foundation, Pavia, Italy Correspondence: Paolo Gresele, MD, PhD, Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via E. dal Pozzo, 06126 Perugia, Italy. E-mail: grespa{at}unipg.it Background: Defects of integrin IIb β 3 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 β 3 -gene ( ITGB3 ) mutation. Results: The characteristics of our families are moderate macrothrombocytopenia and defective platelet function associated with a mild reduction of surface Ib β 3 , impaired platelet aggregation to physiological agonists but not to ristocetin, normal clot retraction, reduced fibrinogen binding and expression of activated IIb β 3 upon stimulation, normal platelet adhesion to immobilized fibrinogen but reduced platelet spreading and tyrosine phosphorylation, indicating defective IIb β 3 -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 β 3 . 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 β 3 , and its βTD domain, in platelet formation and function. Ke