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Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII‐binding capacity
Author(s) -
Hilbert Lysiane,
Jorieux Sylvie,
Proulle Valérie,
Favier Rémi,
Goudemand Jenny,
Parquet Armelle,
Meyer Dominique,
Fressinaud Edith,
Mazurier Claudine
Publication year - 2003
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04163.x
Subject(s) - von willebrand factor , von willebrand disease , missense mutation , exon , microbiology and biotechnology , mutation , point mutation , chemistry , coagulopathy , gene , genetics , biology , medicine , immunology , platelet
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.