title: Mutations in the D'D3 region of VWF traditionally associated with type 1 VWD lead to quantitative and qualitative deficiencies of VWF.
abstract: Type 1 von Willebrand disease (VWD) is characterized by low plasma levels of von Willebrand factor (VWF) and clinical bleeding. Several mechanisms have been described that cause a decrease in plasma VWF levels in VWD, and the goal of this study was to elucidate the pathogenic origins of VWD for a group of mutations in the VWF D'D3 region traditionally associated with type 1 VWD. Varying ratios of mutant-to-wild-type VWF were expressed in two cell lines in order to study the intracellular location, multimer assembly, secretion and function of VWF. We identified four mutants (M771I, Y1146C, T1156M, R782Q) that caused defective intracellular packaging and markedly reduced VWF secretion. Consistent with previous reports, Y1146C and T1156M VWF led to a loss of high molecular weight multimers. In a functional analysis, Y1146C demonstrated a novel FVIII binding defect. Mutations R924W and I1094T were processed normally and did not show abnormal FVIII binding suggesting that other mechanisms such as plasma clearance or platelet binding defects may contribute to the pathogenicity of these mutants.
authors.affiliation: Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: White-Adams
authors.affiliation: Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ng
authors.affiliation: BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Jacobi
authors.affiliation: BloodCenter of Wisconsin, Milwaukee, WI, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
authors.affiliation: Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora, CO, USA; Human Medical Genetics and Genomics, University of Colorado Denver, Aurora, CO, USA. Electronic address: jorge.dipaola@ucdenver.edu.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Di Paola
mesh_terms: D006801:Humans; D009154:Mutation; D014842:von Willebrand Diseases / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor
keywords: D′D3 domain; Quantitative von Willebrand disease; Von Willebrand factor