Summary
Hereditary defects of the von Willebrand factor (VWF) gene cause von Willebrand’s
disease (VWD) which shows great variability dependent on the nature and location of
the mutation. We here describe the characteristics of a substitution of methionine
for threonine 1156 in the D3 domain of the VWF, i.e. the domain involved in the intracellular
multimerization of pro-VWF dimers. A VWD patient with severe symptoms was a compound
heterozygote for the T1156M mutation and a null allele (Q2470X) on the other chromosome.
This led to marked reduction of plasma VWF concentration to about 0.05 U/ml and an
abnormality of VWF multimers as in type 2A VWD. Expression in vitro of the mutation
demonstrated that 1156M-VWF is secreted from COS-7 cells in a much reduced amount
and lacking large multimers. When coexpressed with normal VWF 1156M-VWF decreased
the secretion of normal VWF in a dose-dependent manner, the secreted VWF showing all
the multimers. Two relatives of the propositus were single heterozygotes for the T1156M
mutation and were either asymptomatic or had the manifestations of mild type 1 VWD.
The expression data and studies of platelet VWF indicate that the T1156M mutation
results in intracellular retention of VWF rather than impaired synthesis. Three other
members of the family were heterozygotes for the Q2470X mutation and demonstrated
the variable expressivity of a null allele.
Keywords Von Willebrand’s disease - mutation - COS-7 cell transfection
