POINT MUTATION IN A LEUCINE-RICH REPEAT OF PLATELET GLYCOPROTEIN IB-ALPHA RESULTING IN THE BERNARD-SOULIER SYNDROME

Leucine-rich repeats are a conserved structural motif, of yet undefine d significance, found in a group of proteins from different species. A mong these are the four components of the human platelet glycoprotein Ib-IX-V complex, a membrane receptor that performs an essential role i n the thrombogenic function of platelets by interacting with the adhes ive protein, von Willebrand factor. We have found that a single amino acid substitution (Ala156 --> Val) within one of the six leucine-rich repeats in the alpha-subunit of glycoprotein lb results in a variant f orm of the congenital bleeding disorder, Bernard-Soulier syndrome, cha racterized by giant dysfunctional platelets. Genetic studies of the pr opositus and his family members were complemented by immunological and functional analysis of expressed recombinant GP Ibalpha fragments to demonstrate that the observed mutation is the cause of defective von W illebrand factor binding. These studies define the molecular basis of the Bernard-Soulier syndrome within this family and demonstrate that s tructural integrity of a leucine-rich repeat is necessary for normal f unction of the glycoprotein Ib-IX-V receptor complex and, possibly, fo r normal platelet morphology.