Type IIB von Willebrand disease is characterized by the selective loss of high molecular weight von Willebrand factor (vWF) multimers from plasma and enhanced platelet agglutination of platelet-rich-plasma in the presence of low concentrations of ristocetin. We identified, in two related patients, a C-->G transversion resulting in the substitution of Valine for Leucine at position 697 of the mature subunit of vWF. We reproduced this mutation in vWF cDNA and expressed the recombinant protein in Cos-7 cells. The subunit composition and multimeric structure of mutated protein (rvWFLeu697Val) were similar to the wild- type recombinant (WTrvWF). Ristocetin-induced binding of rvWFLeu697Val to platelets was markedly increased in the presence of low doses of ristocetin and slightly increased with botrocetin as compared with that for WTrvWF, whereas collagen binding was not affected by the mutation. These data show that the Leu 697-->Val substitution is not a rare polymorphism but is responsible for the subtype IIB characteristic abnormalities identified in the two affected patients; however, it is not located in the area of vWF (amino acid 540 to amino acid 578) where most of the other type IIB mutations have already been reported.
Leu 697-->Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease
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L Hilbert, C Gaucher, C de Romeuf, MH Horellou, T Vink, C Mazurier; Leu 697-->Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease. Blood 1994; 83 (6): 1542–1550. doi: https://doi.org/10.1182/blood.V83.6.1542.bloodjournal8361542
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