Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII-binding capacity
- 14 February 2003
- journal article
- research article
- Published by Wiley in British Journal of Haematology
- Vol. 120 (4) , 627-632
- https://doi.org/10.1046/j.1365-2141.2003.04163.x
Abstract
Summary. In type 2N von Willebrand disease (VWD), von Willebrand factor (VWF) is characterized by a markedly decreased affinity for Factor VIII (FVIII), and the mutations responsible are essentially located in the D′ domain of VWF. We report the identification, in seven unrelated French families, of two novel type 2N VWD mutations, Q1053H and C1060R (Gln290His and Cys297Arg in mature VWF sequence), in exon 24 of the VWF gene. These missense mutations have been identified in the heterozygous, homozygous or hemizygous states. Using site‐directed mutagenesis and transient expression in COS‐7 cells, we showed that both mutations, although located in the D3 domain of VWF, outside the tryptic fragment containing the FVIII domain, dramatically decrease the binding of VWF to FVIII. In contrast, the R924Q substitution, which was identified in a patient who was heterozygous for C1060R, was shown to be a polymorphism.Keywords
This publication has 13 references indexed in Scilit:
- Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biologyBest Practice & Research Clinical Haematology, 2001
- Two novel type 2N von Willebrand disease–causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factorBlood, 2000
- Fine epitope mapping of monoclonal antibodies to the NH2‐terminal part of von Willebrand factor (vWF) by using recombinant and synthetic peptides: interest for the localization of the factor VIII binding domainBritish Journal of Haematology, 1994
- Leu 697-->Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand diseaseBlood, 1994
- A Revised Classification of von Willebrand DiseaseThrombosis and Haemostasis, 1994
- The mutation Arg (53)----Trp causes von Willebrand disease Normandy by abolishing binding to factor VIII. Studies with recombinant von Willebrand factorBlood, 1992
- Expression of von Willebrand factor "Normandy": an autosomal mutation that mimics hemophilia A.Proceedings of the National Academy of Sciences, 1991
- A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interactionBlood, 1990
- Identification of disulfide-bridged substructures within human von Willebrand factorBiochemistry, 1987
- Nucleotide sequence of pre-pro-von Willebrand factor cDNANucleic Acids Research, 1986