title: Surface expression of glycoprotein ib alpha is dependent on glycoprotein ib beta: evidence from a novel mutation causing Bernard-Soulier syndrome.
abstract: Bernard-Soulier syndrome is a rare bleeding disorder caused by a quantitative 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 undetectable on the platelet surface. Although confocal imaging confirmed that GPIb alpha was not present on the platelet surface, GPIb alpha was readily detectable in the patient's platelets. Moreover, immunoprecipitation of plasma with 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 beta, resulting in a premature termination of translation at amino acid 21. Studies of transient coexpression of this mutant, W21stop-GPIb beta, together with wild-type GPIbalpha and GPIX, demonstrated a failure of GPIX expression on the surface of HEK 293T cells. Similar results were obtained with Chinese hamster ovary alpha IX cells, a stable cell line expressing GPIbalpha that retains the capacity to re-express GPIX. Thus, we found that GPIbbeta affects the surface expression of the GPIb-IX complex by failing to support the insertion of GPIb alpha and GPIX into the platelet membrane. (Blood. 2000;96:532-539)
authors.affiliation: Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: N
authors.initials: N
authors.lastname: Moran
authors.forename: P A
authors.initials: PA
authors.lastname: Morateck
authors.forename: A
authors.initials: A
authors.lastname: Deering
authors.forename: M
authors.initials: M
authors.lastname: Ryan
authors.forename: R R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: D J
authors.initials: DJ
authors.lastname: Fitzgerald
authors.forename: D
authors.initials: D
authors.lastname: Kenny
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001606:Bernard-Soulier Syndrome / Q000235:genetics*; D001792:Blood Platelets / Q000648:ultrastructure; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry; D006224:Cricetinae; D015870:Gene Expression; D006801:Humans; D007163:Immunosorbent Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D019038:Platelet Glycoprotein GPIb-IX Complex