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Trp207Gly in platelet glycoprotein Ib α is a novel mutation that disrupts the connection between the leucine‐rich repeat domain and the disulfide loop structure and causes Bernard–Soulier syndrome
Author(s) -
ROSENBERG N.,
LALEZARI S.,
LANDAU M.,
SHENKMAN B.,
SELIGSOHN U.,
IZRAELI S.
Publication year - 2007
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.1538-7836.2007.02298.x
Subject(s) - bernard–soulier syndrome , platelet membrane glycoprotein , glycoprotein ib , platelet glycoprotein gpib ix complex , von willebrand factor , mutation , microbiology and biotechnology , western blot , platelet , chemistry , medicine , genetics , biology , glycoprotein , immunology , gene
Summary. Background: Bernard–Soulier syndrome (BSS) is a severe inherited bleeding disorder that is caused by a defect in glycoprotein (GP)Ib‐IX‐V complex, the platelet membrane receptor for von Willebrand factor. Patients: The diagnosis of BSS was made in two members of a Bukharian Jewish family who had life‐long thrombocytopenia associated with mucocutaneous bleeding manifestations. Methods and results: Flow cytometry and Western blot analyses showed only trace amounts of GPIb and GPIX on the patients’ platelets. Sequence analysis of the GPIb α gene revealed a homozygous T > G transversion at nucleotide 709 predicting Trp207Gly substitution in the mature protein. Introduction of the mutation into a mammalian expression construct abolished the surface expression of GPIb α in transfected baby hamster kidney cells. The crystal structure of the N‐terminus of GPIb α (PDB: 1SQ0) indicates that Trp207 is completely buried and located in a disulfide loop structure that interacts with the leucine‐rich repeat (LRR) domain. Conclusion: A novel mutation, Trp207Gly, causes BSS and predicts disruption of the interaction between a disulfide loop and the LRR domain that is essential for the integrity of GPIb α structure.