Molecular defects in the Bernard-Soulier syndrome: assessment of receptor genes, transcripts and proteins.

Bernard-Soulier syndrome involves a multicomponent adhesion receptor on the surface of human platelets. Patients with this disorder bleed excessively from the skin and mucous membranes; and in occasional cases, the bleeding is fatal. At a molecular level, the Bernard-Soulier defect affects the structure and/or function of a receptor that mediates platelet adhesion in the arterial circulation. This receptor, termed glycoprotein (GP) Ib-IX-V, consists of 4 distinct polypeptides (GPs: Ib alpha-143 kDa, Ib beta-22 kDa, IX-20 kDa, V-83 kDa) that share features such as physical associations and leucine-rich glycoprotein (LRG) repeats. All 4 genes and cDNAs have now been cloned and characterized, and the genes have been localized to distinct chromosomal sites. A number of Bernard-Soulier syndrome kindreds have been defined at the molecular genetic level; and in most instances, the defect proved to be a point mutation in either the GP Ib alpha or the GP IX gene. Study of the genetic defects provides insight into both the expression and the function of the receptor. Expression requires the co-ordinated synthesis of the Ib-IX polypeptides with a contribution from GPV. Function of the receptor entails the effect of shear forces generated by blood flow in the artificial circulation. The current challenge in this field is to understand the structure-function relationships within the receptor and its cognate adhesive ligand, von Willebrand factor (vWf).