MOLECULAR DEFECTS IN THE BERNARD-SOULIER SYNDROME - ASSESSMENT OF RECEPTOR GENES, TRANSCRIPTS AND PROTEINS

Bernard-Soulier syndrome involves a multicomponent adhesion receptor o n the surface of human platelets. Patients with this disorder bleed ex cessively from the skin and mucous membranes; and in occasional cases, the bleeding is fatal. At a molecular level, the Bernard-Soulier defe ct affects the structure and/or function of a receptor that mediates p latelet adhesion in the arterial circulation. This receptor termed gly coprotein (GP) Ib-IX-V: consists of 4 distinct polypeptides (GPs: Ib a lpha-143 kDd, Ib beta-22 kDa, IX-20 kDa, V-83 kDa) that share features such as physical associations and leucine-rich glycoprotein (LRG) rep eats. All 4 genes and cDNAs have now been cloned and characterized, an d the genes have been localized to distinct chromosomal sites. A numbe r of Bernard-Soulier syndrome kindreds have been defined at the molecu lar genetic level; and in most instances, the defect proved to be a po int mutation in either the GP Ib alpha: or the GP IX gene. Study of th e genetic defects provides insight into both the expression and the fu nction of the receptor. Expression requires the co-ordinated synthesis of the Ib-IX polypeptides with a contribution from GPV. Function of t he receptor entails the effect of shear forces generated by blood flow in the arterial circulation. The current challenge in this field is t o understand the structure-function relationships within the receptor and its cognate adhesive ligand, von Willebrand factor (vWF).