von Willebrand Disease 2N Gene Mutation Analysis
Von Willebrand Factor Normandy
Factor VIII is stabilized in plasma by complexing with von Willebrand factor. Specific mutations in the factor VIII binding site of von Willebrand factor result in destabilization of this complex causing rapid removal of factor VIII from the circulation1. Three mutations (T791M in exon 18 2, R816W in exon 19 3, and R854Q in exon 20 3) in the von Willebrand factor gene may account for a majority of the Normandy mutations. However, other mutations have been described. The phenotype of these von Willebrand factor Normandy mutations resembles mild hemophilia A showing low factor VIII levels and normal von Willebrand factor levels and multimers. The inheritance of this “pseudo” hemophilia A is autosomal recessive rather than X-linked as is the case for hemophilia A. Mutations altering factor VIII binding are detected by direct DNA sequence analysis of exons 18-20 of the von Willebrand factor gene.
Note on amino acid numbering convention for the von Willebrand factor: Amino acid number 1 corresponds to the first amino acid (met) of the von Willebrand factor propeptide. Removal of the first 763 amino acids of the propeptide results in a mature von Willebrand factor. Previous nomenclature designated the first amino acid of the mature protein (ser) as number 1. The first amino acid of the mature peptide corresponds to amino acid 764 by the current nomenclature. Thus, T791M, R816W and R854Q have previously been designated T28M, R53T and R91Q, respectively.