Genetic studies were performed in two unrelated patients with the IIC phenotype of von Willebrand disease (vWD) characterized by the increased concentration of the protomeric form of von Willebrand factor (vWF). In patient B, the sequencing of both exons 15 and 16 of the vWF gene showed two sequence alterations: a 3-bp insertion in exon 15 resulting in the insertion of a Glycine at position 625 (625insGly) and a 2-bp deletion in exon 16 leading to a premature translational stop at codon 711 (711 ter), at the heterozygote state. Patient A was found homozygous for a single point mutation also localized in exon 15 and responsible for the substitution Cys623Trp. These candidate mutations were not found in a panel of 96 normal chromosomes, suggesting a causal relationship with IIC vWD phenotypic expression. The composite heterozygote or homozygote state of both patients supports the recessive mode of inheritance already described for this phenotype. Furthermore, the localization of these gene defects in the D2 domain of vWF propeptide, known to play an important role in vWF multimerization, provides another argument in favor of their causative effect regarding the peculiar multimeric pattern of vWF in these patients.

This content is only available as a PDF.