In this issue of Blood, Shavit and colleagues take advantage of major differences in von Willebrand factor gene (VWF) expression between inbred mouse strains to identify both a VWF locus alteration (Mvwf5) and 2 unlinked modifier gene loci (Mvwf6-7) that regulate plasma VWF levels.1 

Plasma von Willebrand factor (VWF) plays a key role in hemostasis. In areas of blood vessel injury, it acts as an adhesive link between platelets and components of the extracellular matrix. In addition, it is a carrier for coagulation factor VIII and it serves with fibrinogen as a mediator of platelet-platelet cohesion (aggregation). The inherited disorder of VWF function, von Willebrand disease (VWD), is the most common inherited bleeding disorder in humans and results from quantitative deficiencies in or qualitative abnormalities of VWF. The diagnosis of VWD can often be difficult because of the variety of bleeding symptoms, its variable expressivity, and the incomplete penetrance of VWF mutations. The genetic regulation of VWF expression is complex, not only in humans but also in numerous other mammalian species in which it has been studied. A systematic study of differences in VWF expression between inbred mouse strains has begun to uncover a variety of intriguing mechanisms that control the levels of this important protein. The variety of genetic factors that influence VWF expression is sizable and extends far beyond mutations in the coding sequence or promoter region that directly affect protein function or the rate transcription.

From a genotypic and phenotypic standpoint, inbred mouse strains vary considerably, and one reflection of this genetic divergence is a wide variation in VWF levels, which can range 10-fold or greater between the most divergent strains.2  The Ginsburg group has had unparalleled success in the exploitation of this divergence to dissect many aspects of the genetic basis for VWF variation in mice, and their findings provide new insights into the comparable but even more complex genetic regulation of VWF expression in humans.

In previous work from the Ginsburg group,3  2 major regulators, Mvwf1 and Mvwf2 (modifier of VWF), were discovered. The second regulator Mvwf2 is a natural VWF variant that alters biosynthesis. The discovery of Mvwf1, however, provided new insight into the indirect but profound influence of modifier genes. The culpable gene in Mvwf1 is a glycosyltransferase that influences clearance of VWF. Its influence would otherwise have escaped attention, had it not been for these elegant analyses of inbred mice.

The theme of modifier loci is particularly intriguing and relevant to human disease. Subsequent studies of different mouse strains by the Ginsburg group have uncovered 4 more modifier gene loci that lie outside of the VWF gene: Mvwf3-44  and now Mvwf6-7.1  The existence of such loci is certainly not unique to the mice, and their discovery has implications for the biology of human VWF. Three of these murine loci correlate with potential human modifier loci that exist in the corresponding (syntenic) chromosomal regions. For example, the region that encompasses the human ortholog of Mvwf6 overlaps a region identified as a VWD quantitative trail locus (QTL) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study.5  In addition, it overlaps potential human VWD modifier loci that were identified in a large Amish pedigree.6 

The newly discovered murine loci are admittedly large, each encompassing several genes. Nonetheless, the Ginsburg group has already shown that positional cloning is likely to identify candidate genes within these loci that will point the way to the discovery of additional human genes that influence risk for bleeding or thrombosis. This sentinel body of work demonstrates how great benefits to mankind can follow from a mischief of mice.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

REFERENCES

REFERENCES
1
Shavit
 
JA
Manichaikul
 
A
Lemmerhirt
 
HL
Broman
 
KW
Ginsburg
 
D
Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice.
Blood
2009
, vol. 
114
 
26
(pg. 
5368
-
5374
)
2
Westrick
 
RJ
Ginsburg
 
D
Modifier genes for disorders of thrombosis and hemostasis.
J Thromb Haemost
2009
, vol. 
7
 
suppl 1
(pg. 
132
-
135
)
3
Mohlke
 
KL
Purkayastha
 
AA
Westrick
 
RJ
, et al. 
Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase.
Cell
1999
, vol. 
96
 
1
(pg. 
111
-
120
)
4
Lemmerhirt
 
HL
Broman
 
KW
Shavit
 
JA
Ginsburg
 
D
Genetic regulation of plasma von Willebrand factor levels: quantitative trait loci analysis in a mouse model.
J Thromb Haemost
2007
, vol. 
5
 
2
(pg. 
329
-
335
)
5
Souto
 
JC
Almasy
 
L
Soria
 
JM
, et al. 
Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project.
Thromb Haemost
2003
, vol. 
89
 
3
(pg. 
468
-
474
)
6
Di Paola
 
J
Rickard
 
M
Murray
 
J
Burns
 
T
Wang
 
K
Shapiro
 
A
A genome-wide linkage scan of a large Amish pedigree with von Willebrand disease (VWD) identified several chromosomal regions that may contain potential modifiers of von Willebrand factor (VWF) levels and disease variability [abstract].
Blood
2006
, vol. 
108
 
11
 
Abstract 176