title: A novel Phe171Cys mutation in integrin alpha causes Glanzmann thrombasthenia by abrogating alphabeta complex formation.
abstract: BACKGROUND
  Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterized by lack of platelet aggregation induced by most agonists. The disease is caused by mutations in either alpha(IIb)[glycoprotein (GP) IIb] or beta(3) (GPIIIa) genes that lead to a lack or dysfunction of the integrin alpha(IIb)beta(3) which serves as a fibrinogen receptor.
  
  
  METHODS
  Mucocutaneous bleeding manifestations and platelet dysfunction consistent with GT were observed in three members of a Cypriot family: a 3-year-old proband, her father and her paternal uncle.
  
  
  OBJECTIVE
  To determine the molecular basis of GT in this family and to characterize possible biochemical and structural defects.
  
  
  RESULTS
  Analysis of the patients' platelets by fluorescence-activated cell sorting demonstrated trace amounts of beta(3), no alpha(IIb) and no alpha(IIb)beta(3) on the membrane. Sequence analysis revealed a novel T607G transversion in exon 5 of the alpha(IIb) gene predicting a Phe171Cys alteration that created a PstI recognition site. All three patients were homozygous for the mutation, the mother and paternal grandparents of the proband were heterozygous, whereas 110 healthy subjects lacked this transversion. Chinese hamster ovary cells cotransfected with cDNAs of mutated alpha(IIb) and wild-type beta(3) failed to express alpha(IIb)beta(3) as shown by immunoprecipitation and immunohistochemistry experiments. Structural analysis of the alpha(IIb)beta(3) model, which was based on the crystal structure of alpha(v)beta(3), indicated that Phe171 plays an essential role in the interface between the beta-propeller domain of alpha(IIb) and the betaA domain of beta(3).
  
  
  CONCLUSIONS
  A novel Phe171Cys mutation in the alpha(IIb) gene of patients with GT is associated with abrogation of alpha(IIb)beta(3) complex formation.
authors.affiliation: Amalia Biron Research Institute of Thrombosis and Hemostasis, Safra Children's Hospital, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Rosenberg
authors.forename: M
authors.initials: M
authors.lastname: Landau
authors.forename: J
authors.initials: J
authors.lastname: Luboshitz
authors.forename: G
authors.initials: G
authors.lastname: Rechavi
authors.forename: U
authors.initials: U
authors.lastname: Seligsohn
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000737:chemistry; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000502:physiology*; D010375:Pedigree; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D013915:Thrombasthenia / Q000209:etiology / Q000235:genetics*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb