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Jingrong Tang, Sara Stern-Nezer, Po-Ching Liu, Ludmila Matyakhina, Michael Riordan, Naomi L. C. Luban, Peter J. Steinbach, Stephen G. Kaler
Mutation in the leucine-rich repeat C-flanking region of platelet glycoprotein Ib impairs assembly of von Willebrand factor receptor
We describe a syndrome of thrombocytopenia, bleeding episodes, congenital heart disease and facial dysmorphism in a newborn infant, and trace the cause to mutations on chromosome 22 that involve the gene for platelet glycoprotein Ib (GPIb, Human Genome Organisation gene symbol GPIBB), a critical component of the von Willebrand factor (vWF) receptor. Fluorescence in situ hybridization in transformed lymphoblasts revealed hemizygous microdeletion of 22q11.2 containing the GP1BB locus. DNA sequencing revealed a C to T transition in the patient's remaining GP1BB allele, predicting a novel proline to serine substitution (Pro96Ser) in the carboxyterminal flanking domain of a leucine-rich repeat. We characterized the mutant GP1BB allele by expression in a cell line (CHOIX) that stably expresses two other components of the vWF receptor, GPIb and GPIX. Flow cytometry and confocal imaging of transfected CHOIX cells demonstrated that P96S GPIb abrogates surface assembly of the complex, consistent with platelet flow cytometry studies in the patient. Based on sequence homology to the known crystal structures of two other leucine-rich repeat proteins, the human Nogo receptor and GPIb, we propose a new structural model of GPIb. The model refutes earlier assumptions about cysteine-cysteine interactions in the amino-terminal region of GPIb, and predicts a hydrophobic patch the burial of which may contribute to proper conformation of the fully assembled vWF receptor complex.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 92, 07/2004
Pages: 75 - 88