title: Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome.
abstract: Leucine-rich repeats are a conserved structural motif, of yet undefined significance, found in a group of proteins from different species. Among these are the four components of the human platelet glycoprotein Ib-IX-V complex, a membrane receptor that performs an essential role in the thrombogenic function of platelets by interacting with the adhesive 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 Ib results in a variant form of the congenital bleeding disorder, Bernard-Soulier syndrome, characterized by giant dysfunctional platelets. Genetic studies of the propositus and his family members were complemented by immunological and functional analysis of expressed recombinant GP Ib alpha fragments to demonstrate that the observed mutation is the cause of defective von Willebrand factor binding. These studies define the molecular basis of the Bernard-Soulier syndrome within this family and demonstrate that structural integrity of a leucine-rich repeat is necessary for normal function of the glycoprotein Ib-IX-V receptor complex and, possibly, for normal platelet morphology.
authors.affiliation: Roon Research Laboratory for Arteriosclerosis and Thrombosis, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037.
authors.forename: J
authors.initials: J
authors.lastname: Ware
authors.forename: S R
authors.initials: SR
authors.lastname: Russell
authors.forename: P
authors.initials: P
authors.lastname: Marchese
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: M
authors.initials: M
authors.lastname: Mazzucato
authors.forename: L
authors.initials: L
authors.lastname: De Marco
authors.forename: Z M
authors.initials: ZM
authors.lastname: Ruggeri
mesh_terms: D000595:Amino Acid Sequence; D001606:Bernard-Soulier Syndrome / Q000235:genetics*; D016384:Consensus Sequence; D000939:Epitopes; D006801:Humans; D008969:Molecular Sequence Data; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D017354:Point Mutation
chemical_list: D000939:Epitopes; D010980:Platelet Membrane Glycoproteins