Identification of new type 2B von Willebrand disease mutations: Arg543Gln, Arg545Pro and Arg578Leu

• Published in: British journal of haematology Vol. 103; no. 3; pp. 877 - 884
• Main Authors: Hilbert, L., Gaucher, C., Abgrall, J. F., Parquet, A., Trzeciak, C., Mazurier, C.
• Format: Journal Article
• Language: English
• Published: Oxford, U.K. and Cambridge, USA Blackwell Science Ltd 01.12.1998; Blackwell; Blackwell Publishing Ltd
• Subjects: Adolescent; Adult; Amino Acid Substitution - genetics; Biological and medical sciences; Cos‐7 cells; Female; Hematologic and hematopoietic diseases; Hematology; Hemorrhagic Disorders - genetics; Heterozygote; Humans; Male; Medical sciences; Middle Aged; Mutation; Pedigree; Phenotype; Platelet diseases and coagulopathies; recombinant protein; type 2B mutation; von Willebrand disease; von Willebrand Diseases - genetics; von Willebrand factor; von Willebrand Factor - genetics; Human; Family study; Willebrand disease; Clinical form; Male; Hemopathy; Genetic disease; Case study; Gene; Adolescent; Genetics; Adult; Female; Mutation; Willebrand factor; Coagulopathy
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1998.01040.x

We report the identification in five patients (three families) affected with type 2B von Willebrand disease (VWD) of three heterozygous nucleotide substitutions at the codon for arginine 543, 545 and 578 of the mature von Willebrand factor (VWF) subunit resulting in a glutamine, proline and leucine substitution, respectively. These mutations are located in the A1 loop where prevalent type 2B mutations (Arg543Trp, Arg545Cys and Arg578Gln) have been already identified at the same positions. By in vitro mutagenesis of full‐length cDNA of VWF and transient expression in Cos‐7 cells, we have shown that the six corresponding mutated recombinant VWFs (Gln543, Trp543, Cys545, Pro545, Leu578 and Gln578 rVWF) exhibited quantitatively normal expression and normal multimeric pattern but increased ristocetin‐ and botrocetin‐induced binding to platelets as compared with that for wild‐type rVWF. The two mutations at position 545 induced the greatest reactivity for GPIb of corresponding rVWFs as compared to the two mutations at positions 543 and 578.