Im. Nesbitt et al., A common splice site mutation is shared by two families with different type 2N von Willebrand disease mutations, THROMB HAEM, 82(3), 1999, pp. 1061-1064
Using an ELISA-based method to detect type 2N von Willebrand disease (VWD),
we found two individuals with absent FVIII binding. Direct sequencing of t
he FVIII binding region of the von Willebrand factor (VWF) gene showed that
one individual had an R854Q substitution whilst the other had a T791M subs
titution. The very low FVIII binding and the VWF:Ag levels in both individu
als suggested a second defect on the other VWF allele. Conformation sensiti
ve gel electrophoresis of polymerase chain reaction amplified DNA was used
to detect an additional change in the VWF gene of each patient. Direct sequ
encing confirmed a previously unreported G to A transition in the donor spl
ice site in intron 25 of both individuals which should result in a null all
ele. This was confirmed by mRNA analysis, These two individuals therefore h
ave compound heterozygous VWD in which the only expressed allele has a type
2N mutation. In our population, such compound heterozygosity appears to be
a significant cause of type 2N VWD.