title: Dominant inheritance of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families.
abstract: BACKGROUND
  Defects of integrin alpha(IIb)beta(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.
  
  
  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 beta(3)-gene (ITGB3) mutation.
  
  
  RESULTS
  The characteristics of our families are moderate macrothrombocytopenia and defective platelet function associated with a mild reduction of surface alpha(Ib) beta(3), impaired platelet aggregation to physiological agonists but not to ristocetin, normal clot retraction, reduced fibrinogen binding and expression of activated alpha(IIb)beta(3) upon stimulation, normal platelet adhesion to immobilized fibrinogen but reduced platelet spreading and tyrosine phosphorylation, indicating defective alpha(IIb)beta(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 betaTD ectodomain of integrin beta(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 beta(3), and its betaTD domain, in platelet formation and function.
authors.affiliation: Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via E. dal Pozzo, Perugia, Italy. grespa@unipg.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
authors.forename: Emanuela
authors.initials: E
authors.lastname: Falcinelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Giannini
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Angela
authors.initials: A
authors.lastname: D'Eustacchio
authors.forename: Teresa
authors.initials: T
authors.lastname: Corazzi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Mezzasoma
authors.forename: Filomena
authors.initials: F
authors.lastname: Di Bari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Guglielmini
authors.forename: Luca
authors.initials: L
authors.lastname: Cecchetti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia