Glycoprotein (GP)Ib-IX complex is a highly expressed receptor complex on the platelet surface and plays a critical role in platelet activation and clearance. It consists of GPIbα, GPIbβ and GPIX subunits, with GPIbα containing the ligand-binding domain for von Willebrand factor (VWF) and other hemostatically important proteins. Bernard-Soulier syndrome (BSS), a rare hereditary bleeding disorder, is characterized by the abnormally low expression of functional GPIbα on the platelet surface. Previous studies of GPIb-IX expression in platelets and transfected Chinese hamster ovary (CHO) cells have showed that efficient surface expression of GPIbα requires its coexpression and proper assembly with GPIbβ and GPIX. However, the molecular basis underlying the fast degradation and low surface expression of GPIbα in the absence of GPIbβ and GPIX has remained unclear. Since the recently identified mechanosensory domain of GPIbα is not stable in isolation, we tested here whether it plays a role in influencing GPIbα expression in transfected CHO cells. Removal of this domain produced the first GPIbα variant (GPIbαΔ417-483) that could express alone in the plasma membrane at a level comparable to that of GPIbα in the wild-type GPIb-IX complex. Further analysis of mutational effects on GPIbα expression detected by flow cytometry and Western blot suggests that in the absence of GPIbβ and GPIX residues 461-483 confer GPIbα the vulnerability to degradation and low surface expression in transfected CHO cells. The underlying reason is being explored, but it is not due to the heightened exposure of the ADAM17 cleavage site because surface expression levels of various GPIbα variants in transfected CHO M2 cells, which lack a functional ADAM17, was very similar to those in wild-type CHO cells. In conclusion, we have identified for the first time high-expressing GPIba variants that retain native VWF-binding activity and intracellular signaling sequence, which will help to shed important insights on BSS pathogenesis and GPIb-IX structure-function.