Novel cysteine substitution p.(Cys1084Tyr) causes variable expressivity of qualitative and quantitative VWF defects.

von Willebrand factor (VWF) is an extremely cysteine-rich multimeric protein that is essential for maintaining normal hemostasis. The cysteine residues of VWF monomers form intra- and intermolecular disulfide bonds that regulate its structural conformation, multimer distribution, and ultimately its hemostatic activity. In this study, we investigated and characterized the molecular and pathogenic mechanisms through which a novel cysteine variant p.(Cys1084Tyr) causes an unusual, mixed phenotype form of von Willebrand disease (VWD). Phenotypic data including bleeding scores, laboratory values, VWF multimer distribution, and desmopressin response kinetics were investigated in 5 members (2 parents and 3 daughters) of a consanguineous family. VWF synthesis and secretion were also assessed in a heterologous expression system and in a transient transgenic mouse model. Heterozygosity for p.(Cys1084Tyr) was associated with variable expressivity of qualitative VWF defects. Heterozygous individuals had reduced VWF:GPIbM (<0.40 IU/mL) and VWF:CB (<0.35 IU/mL), as well as relative reductions in high-molecular-weight multimers, consistent with type 2A VWD. In addition to these qualitative defects, homozygous individuals also displayed reduced factor VIII (FVIII):C/VWF:Ag, leading to very low FVIII levels (0.03-0.1 IU/mL) and reduced VWF:Ag (<0.40 IU/mL) and VWF:GPIbM (<0.30 IU/mL). Accelerated VWF clearance and impaired VWF secretion contributed to the fully expressed homozygous phenotype with impaired secretion arising because of disordered disulfide connectivity.