Comment on Lemmerhirt et al, page 3061
von Willebrand disease is a heterogeneous bleeding disorder in which the von Willebrand factor is abnormal in concentration, function, and/or structure. Each of these properties has a variable effect on the clinical and laboratory phenotype.
Human von Willebrand disease (VWD), particularly type 1 VWD, continues to be a clinically baffling disorder.1 Two recent large VWD studies have identified families with low VWF that can be either genetically linked or nonlinked with the VWF gene.2,3 While the spectrum of genetic mutations causing low VWF is wide4,5 and may not be applicable across different species, studying broad mechanisms using inbred strains offers the opportunity to identify the spectrum of alterations that result in an increase or a decrease in VWF levels.
It is clear in the mouse that markedly different plasma levels have been selected through inbreeding and natural derivation of mouse strains. Since mouse strains have up to a 20-fold difference in levels of plasma VWF,6 they offer a unique model to identify variable mechanisms for producing such marked variation. Some of these mechanisms are extragenic causes, such as the Mvwf1 modifier previously reported by this group7 that alters VWF clearance by means of altered glycosylation. In this issue of Blood, Lemmerhirt and colleagues report an intragenic variation within the VWF gene that results in a 20-fold greater level of VWF, and, notably, the alteration in the CASA/RkJ is a change that is present in human VWF but not in a variety of other inbred mouse strains. Whether this mutation results in increased biosynthesis and/or secretion, or decreased clearance, is not yet clear. Nevertheless, sequence differences can obviously account for differences in plasma levels that bracket the differences seen in humans—both in healthy individuals (50%-150% of normal) as well as those with VWD (10%-20% of normal). Whether this variability in murine VWF has been selected by chance during inbreeding or by natural biologic selection is not clear. This will undoubtedly be the subject of further study. The study also suggests that there is the biological possibility that human VWF gene alterations may potentially increase or decrease plasma VWF—although thus far only mutations that decrease VWF levels have been identified.4,5
The heterogeneity in our understanding of VWF and VWD continues. We will probably find VWF alterations that produce elevated VWF in humans, another variable to consider in our clinical diagnosis of VWD and the variability found within even a single family. Mice and creative scientists, including Lemmerhirt et al in this issue of Blood, continue to push our understanding of human biology. ▪
