von Willebrand Disease (vWD) is the most common inherited bleeding disorder in humans. Type I vWD, which accounts for approximately 70% of cases, is typically a mild hemorrhagic diathesis due to a quantitative defect in von Willebrand factor (vWF). Recently, molecular defects resulting in some of the Type II (qualitative) variants have been described within the vWF gene. Gene deletions and nonsense mutations in vWF have been recognized in some patients with Type III or severe vWD. The molecular basis for Type I vWD, however, remains unknown. Furthermore, there is no conclusive evidence that Type I vWD is linked to the vWF gene in humans. In this proposal, we plan to study the molecular pathogenesis of both human and murine Type I vWD. In collaboration with Swank and coworkers at Roswell Park Cancer Institute, we have studied an inbred strain of mice, RIIIS/J, that has a bleeding disorder remarkably similar to human Type I vWD. This bleeding diathesis is inherited in an autosomal dominant pattern as is the human form. Preliminary genetic studies in which RIIIS/J was crossed with an inbred strain of Mus spretus revealed that low vWF levels in the RIIIS/J mouse strain are due to defects outside the murine vWF gene. Analyses of human Type I vWD pedigrees will be performed using polymorphisms in the vWF gene to determine if there is linkage of any of the forms of Type I vWD to the vWF gene. Further analysis of murine vWD will be undertaken by using polymorphic short tandem repeats saturating the mouse genome to search for a genetic factor(s) contributing to this quantitative defect in vWF. Positional cloning techniques will subsequently be used to identify candidate genes in the mouse responsible for Type I vWD. Human Type I vWD families in which linkage to the vWF gene has been excluded will be assessed for defects in the homologous gene. This work will ultimately have important implications for the diagnosis and treatment of human Type I vWD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002839-03
Application #
2210657
Study Section
Special Emphasis Panel (ZHL1-CCT-M (02))
Project Start
1993-07-01
Project End
1996-02-29
Budget Start
1995-07-01
Budget End
1996-02-29
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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