Surface expression of glycoprotein Ib alpha is dependent on glycoprotein Ib beta: evidence from a novel mutation causing Bernard-Soulier syndrome

Bernard-Soulier syndrome is a rare bleeding disorder caused by a quantitati ve or qualitative defect in the platelet glycoprotein (GP) Ib-IX-V complex. The complex, which serves as a platelet receptor for von Willebrand factor , is composed of 4 subunits: GPIb alpha, GPIb beta, GPIX, and GPV. We here describe the molecular basis of a novel form of Bernard-Soulier syndrome in a patient in whom the components of the GPIb-IX-V complex were undetectabl e on the platelet surface. Although confocal imaging confirmed that GPIb al pha was not present on the platelet surface, GPIb alpha was readily detecta ble in the patient's platelets. Moreover, immunoprecipitation of plasma wit h specific monoclonal antibodies identified circulating, soluble GPIb alpha , DNA-sequence analysis revealed normal sequences for GPIb alpha and GPIX, There was a G to A substitution at position 159 of the gene encoding GPIb b eta, resulting in a premature termination of translation at amino acid 21, Studies of transient coexpression of this mutant, W21stop-GPIb beta, togeth er with wild-type GPIb alpha and GPIX, demonstrated a failure of GPIX expre ssion on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary or IX cells, a stable cell line expressing GPIba that retains the capacity to re-express GPIX, Thus, we found that GPIb beta aff ects the surface expression of the GPIb-IX complex by failing to support th e insertion of GPIb alpha and GPIX into the platelet membrane. (C) 2000 by The American Society of Hematology.