Article ; Online: Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.
Research and practice in thrombosis and haemostasis
2022 Volume 6, Issue 4, Page(s) e12737
Abstract: Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (: Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/ ... ...
| Abstract | Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene ( Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results: Homozygous expression of the p.(Cys2216Phefs*9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)-rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild-type-rVWF. Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects. |
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| Language | English |
| Publishing date | 2022-06-15 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2475-0379 |
| ISSN (online) | 2475-0379 |
| DOI | 10.1002/rth2.12737 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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