Kozak sequence polymorphism of the glycoprotein (GP) Ib alpha gene is a major determinant of the plasma membrane levels of the platelet GP Ib-IX-V complex

Despite the known importance of the sequences surrounding ATG start codons (Kozak sequences) for efficient translation of proteins, few reports have a ppeared that describe the natural variations in these sequences. Here, we r eport a human polymorphism in the Kozak sequence of the platelet adhesion r eceptor, glycoprotein (GP) Ib alpha, a component of the GP Ib-IX-V complex, which mediates the initial adhesion of platelets to the blood vessel wall following injury. The polymorphism is based on the presence of either thymi ne (T) or cytosine (C) at position -5 from the initiator ATG in the GP Ib a lpha gene. The less common allele, -5C, represented 8% to 17% of the allele s in four ethnic populations surveyed. This allele more closely resembles t he sequence considered optimal for efficient initiation of protein translat ion and is associated with increased expression of the receptor on the cell membrane, both in transfected cells and in the platelets of individuals ca rrying the allele. In vitro transcription/ translation studies indicate tha t the increased expression results from more efficient translation of the - 5C form of the GP Ib alpha mRNA. Other mutations made to approximate more c losely the consensus sequence described by Kozak did not increase expressio n of the receptor. This is the first known description of Kozak sequence po lymorphism as a determinant of the surface levels of a cell adhesion recept or. This polymorphism may influence an individual's susceptibility for the development of cardiovascular disease. (C) 1999 by The American Society of Hematology.