title: A novel polymorphism, 70Leu/Phe, disrupts a consensus Leu residue within the leucine-rich repeat sequence of platelet glycoprotein Ibalpha.
abstract: Platelet glycoprotein (GP) Ib/IX/V complex mediates high-shear dependent platelet activation through an interaction with the von Willebrand factor (vWF). All four subunits of the complex have a structural motif, the leucine-rich repeat (LRR) sequence, with leucines in conserved positions. Here we report a new polymorphism, Leu/Phe at residue 70 of GPIbalpha, which disrupts the consensus sequence of the LRR in the vWF binding domain. Genotype frequencies among 142 healthy Japanese subjects were 92.3%, 7.7%, and 0.0%, for the 70Leu/Leu, 70Leu/Phe, and 75Phe/Phe genotypes, respectively. Ristocetin-induced or shear-induced platelet aggregation was not significantly different between the 70Leu/Leu and 70Leu/Phe genotypes. In in vitro studies, a recombinant GPIbalpha fragment with 70Phe (L70F) as compared to that with 70Leu (WT) had low reactivity to anti-GPIbalpha monoclonal antibodies, GUR20-5 and Hip1, both of which recognize conformation-specific epitopes within the 45-kDa domain. Ristocetin-induced 125I-vWF binding to L70F, however, did not differ from that to WT.
authors.affiliation: Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Murata
authors.forename: Takanori
authors.initials: T
authors.lastname: Moriki
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Naohide
authors.initials: N
authors.lastname: Watanabe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Makoto
authors.initials: M
authors.lastname: Handa
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawano
authors.forename: Nobuo
authors.initials: N
authors.lastname: Aoki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yoshino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D044466:Asian People / Q000235:genetics; D001792:Blood Platelets / Q000276:immunology; D016466:CHO Cells; D016384:Consensus Sequence; D006224:Cricetinae; D003412:Cricetulus; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D007930:Leucine; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000276:immunology; D010974:Platelet Aggregation / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics*; D012310:Ristocetin / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D012310:Ristocetin; D007930:Leucine