Homozygous type 2N R854W von Willebrand factor is poorly secreted and causes a severe von Willebrand disease phenotype

摘要: Summary. Background: von Willebrand disease (VWD) type Normandy (VWD 2N) is caused by mutations at the factor (F)VIII-binding site of von (VWF), located in D′and D3 domains on N-terminus mature VWF. The R854Q mutation most frequent cause this phenotype. Objectives: We report characterization a homozygous VWD 2N mutation, R854W, detected patient with severe VWD Methods: The plasma VWF phenotype was studied, transient expression recombinant mutant full-length 293 EBNA cells performed, and results were compared those obtained wild-type (WT) Furthermore, also examined HEK293 cells, which form Weibel–Palade body-like granules when transfected WT Results: The multimer analysis showed lack typical triplet structure, presence central band only, relative decrease high molecular mass multimers. Homozygous R854W resulted normal amounts cellular VWF, but reduction secretion into medium. Severe reductions FVIII binding to glycoprotein Ib activity collagen secreted W854 observed, reproduced phenotypic parameters In failed granules. Conclusions: Our demonstrate that D′ domain induces impaired protein, thereby explaining patient.