Mutation in the leucine-rich repeat C-flanking region of platelet glycoprotein Ibβ impairs assembly of von Willebrand factor receptor

摘要: We describe a syndrome of thrombocytopenia, bleeding episodes, congenital heart disease and facial dysmorphism in newborn infant, trace the cause to mutations on chromosome 22 that involve gene for platelet glycoprotein Ibs (GPIbβ, Human Genome Organisation symbol GPIBB), critical component von Willebrand factor (vWF) receptor. Fluorescence situ hybridization transformed lymphoblasts revealed hemizygous microdeletion 22q11.2 containing GP1BB locus. DNA sequencing C T transition patient’s remaining allele, predicting novel proline serine substitution (Pro96Ser) carboxyterminal flanking domain leucine-rich repeat.We characterized mutant allele by expression cell line (CHOαIX) stably expresses two other components vWF receptor, GPIbα GPIX. Flow cytometry confocal imaging transfected CHOαIX cells demonstrated P96S GPIbβ abrogates surface assembly complex, consistent with flow studies patient. Based sequence homology known crystal structures repeat proteins, human Nogo receptor GPIbα, we propose new structural model GPIbβ.The refutes earlier assumptions about cysteine-cysteine interactions amino-terminal region GPIbβ, predicts hydrophobic patch burial which may contribute proper conformation fully assembled complex.