N1421K mutation in the glycoprotein Ib binding domain impairs ristocetin- and botrocetin-mediated binding of von Willebrand factor to platelets

Autor: Christina Isaksson, Ann-Charlotte Kristoffersson, Stefan Lethagen, Elsa Lanke, Lars Holmberg
Rok vydání: 2008
Předmět:
Blood Platelets
Male
Von Willebrand factor type C domain
Heterozygote
congenital
hereditary
and neonatal diseases and abnormalities
Platelet Aggregation
Mutation
Missense
chemistry.chemical_compound
Platelet Adhesiveness
Von Willebrand factor
hemic and lymphatic diseases
Chlorocebus aethiops
Crotalid Venoms
von Willebrand Factor
Von Willebrand disease
medicine
Animals
Humans
Family
Platelet
Ristocetin
Binding Sites
Factor VIII
biology
Chemistry
Hematology
General Medicine
medicine.disease
Molecular biology
Anti-Bacterial Agents
Pedigree
Protein Structure
Tertiary
von Willebrand Diseases
Amino Acid Substitution
Platelet Glycoprotein GPIb-IX Complex
Glycoprotein Ib
Coagulation
COS Cells
Immunology
biology.protein
Female
Collagen
Protein Binding
circulatory and respiratory physiology
Binding domain
Zdroj: European Journal of Haematology.
ISSN: 1600-0609
0902-4441
DOI: 10.1111/j.1600-0609.2008.01123.x
Popis: von Willebrand disease (VWD) is a common inheritable bleeding disorder caused by deficiency of von Willebrand Factor (VWF), which is involved in platelet adhesion and aggregation. We report a family consisting of three patients with VWD characterized by an apparently normal multimeric pattern, moderately decreased plasma factor VIII (FVIII) and VWF levels, and disproportionately low plasma VWF:RCo levels. The patients were found to be heterozygous for the novel N1421K mutation, caused by a 4263C>G transversion in exon 28 of the VWF gene coding for the A1 domain. Botrocetin- and ristocetin-mediated binding of plasma VWF to GPIb were reduced in the patients. In vitro mutagenesis and expression in COS-7 cells confirmed the impairment of the mutant in botrocetin- and ristocetin-mediated VWF binding to GPIb. VWF collagen binding capacity was unaffected in plasma from the heterozygous individuals as well as in medium from transfected COS-7 cells. Our findings indicate that the N1421K substitution in the VWF affects the GPIb binding site or a recognition element by a conformational change of the A1 domain. (Less)
Databáze: OpenAIRE
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