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

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.