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A novel Phe171Cys mutation in integrin α IIb causes Glanzmann thrombasthenia by abrogating α IIb β 3 complex formation
Author(s) -
Rosenberg N.,
Landau M.,
Luboshitz J.,
Rechavi G.,
Seligsohn U.
Publication year - 2004
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2004.00758.x
Subject(s) - transversion , proband , exon , platelet membrane glycoprotein , mutation , microbiology and biotechnology , glanzmann's thrombasthenia , genetics , biology , platelet , thrombasthenia , medicine , gene , glycoprotein , platelet aggregation
Summary. 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 α IIb [glycoprotein (GP) IIb] or β 3 (GPIIIa) genes that lead to a lack or dysfunction of the integrin α IIb β 3 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 β 3 , no α IIb and no α IIb β 3 on the membrane. Sequence analysis revealed a novel T607G transversion in exon 5 of the α IIb gene predicting a Phe171Cys alteration that created a Pst I 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 α IIb and wild‐type β 3 failed to express α IIb β 3 as shown by immunoprecipitation and immunohistochemistry experiments. Structural analysis of the α IIb β 3 model, which was based on the crystal structure of α v β 3 , indicated that Phe171 plays an essential role in the interface between the β‐propeller domain of α IIb and the βA domain of β 3 . Conclusions : A novel Phe171Cys mutation in the α IIb gene of patients with GT is associated with abrogation of α IIb β 3 complex formation.