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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 186-191
Kozak Sequence Polymorphism of the Glycoprotein (GP) Ib Gene Is a
Major Determinant of the Plasma Membrane Levels of the Platelet GP
Ib-IX-V Complex
Vahid Afshar-Kharghan,
Chester Q. Li,
Mohammad Khoshnevis-Asl, and
José A. López
From the Departments of Medicine and Molecular and Human Genetics,
Baylor College of Medicine and Veterans Affairs Medical Center,
Houston, TX.
Despite the known importance of the sequences surrounding ATG start
codons (Kozak sequences) for efficient translation of proteins, few
reports have appeared that describe the natural variations in these
sequences. Here, we report a human polymorphism in the Kozak sequence
of the platelet adhesion receptor, glycoprotein (GP) Ib , 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 thymine (T) or cytosine (C) at
position  5 from the initiator ATG in the GP Ib gene. The less
common allele, 5C, represented 8% to 17% of the alleles in four
ethnic populations surveyed. This allele more closely resembles the
sequence considered optimal for efficient initiation of protein
translation and is associated with increased expression of the receptor
on the cell membrane, both in transfected cells and in the platelets of
individuals carrying the allele. In vitro transcription/translation
studies indicate that the increased expression results from more
efficient translation of the 5C form of the GP Ib mRNA. Other
mutations made to approximate more closely the consensus sequence
described by Kozak did not increase expression of the receptor. This is
the first known description of Kozak sequence polymorphism as a
determinant of the surface levels of a cell adhesion receptor. This
polymorphism may influence an individual's susceptibility for the
development of cardiovascular disease.
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