A novel Phe171Cys mutation in integrin αIIb causes Glanzmann thrombasthenia by abrogating αIIbβ3 complex formation

N. Rosenberg, M. Landau, J. Luboshitz, G. Rechavi, Uri Seligsohn

Research output: Contribution to journalArticlepeer-review

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 αIIb [glycoprotein (GP) IIb] or β3 (GPIIIa) genes that lead to a lack or dysfunction of the integrin αIIbβ3 which serves as a fibrinogen receptor. Patients 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 β3, no αIIb and no αIIbβ3 on the membrane. Sequence analysis revealed a novel T607G transversion in exon 5 of the αIIb 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 αIIb and wild-type β3 failed to express αIIbβ3 as shown by immunoprecipitation and immunohistochemistry experiments. Structural analysis of the αIIbβ3 model, which was based on the crystal structure of αvβ3, indicated that Phe171 plays an essential role in the interface between the β-propeller domain of αIIb and the βA domain β3. Conclusions: A novel Phe171Cys mutation in the αIIb gene of patients with GT is associated with abrogation of αIIbβ3 complex formation.

Original languageEnglish
Pages (from-to)1167-1175
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume2
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

Keywords

  • Glanzmann thrombasthenia
  • Integrin
  • α mutation
  • αβ

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