The Genetics of Von Willebrand Disease
by Michael Alimario
It was in 1931 that a man by the name of von Willebrand first described a peculiar bleeding disorder amongst the Aaland Islanders in the Gulf of Bothnia. Today von Willebrand disease is recognized as the most common hereditary bleeding disorder that may occur in up to 1% of the population. Although the condition is known to be inherited as an autosomal dominant (affecting both males and females) individuals may also acquire the disease through a production of antibody that decreases the plasma concentration of von Willebrand factor.
Von Willebrand factor is the plasma protein which is deficient and/ or defective in the disease. This factor is what causes platelets to bind damaged blood vessel walls which aids in the termination of bleeding (hemostaisis). Therefore sufferers who have the disease either yield a protein that does not function properly or exhibit diminished production of the vW factor- hence resulting in platelets that do not adhere properly when blood vessels are injured and longer overall bleeding times.
Numerous studies conducted on the von Willebrand factor gene have yielded partial cDNA clones through such processes as sequential cleavage and re-ligation of restriction fragments derived from overlapping cDNA clones. The resulting identity reveals a cDNA clone of approximately 8794 bp with all of the DNA bases represented in the mature protein product of the vWF gene. The gene itself spans some 178kb and comprises 51 introns (between 97 bp and 19.9 kb in length) and 52 exons (between 40 and 1379 bp in length).
The von Willebrand factor is usually absent in individuals who have the severe form of the disease (type III). Joint and muscle hemorrhages are common symptoms of this extreme condition and can be associated with a severe decrease in clotting factor VIII (the protein absent in hemophilia A). In one particular case Swedish researchers sequenced the vWF gene from 25 patients with the type III form of the disease. They discovered a transition and missense point mutation that altered a CGA m RNA codon to a UGA codon. Of the 25 patients studied, one was found to have this particular mutation in an intron, where it introduces a new recognition site for the restriction enzyme DdeI.
Within the scope of the severe form of the disorder a degree of phenotypic heterogeneity has been detected amongst obligatory heterozygote relatives of patients with the type III disease. The condition appears to be more common in the Middle East where consanguineous marriage is accepted. Until recently molecular analysis of point mutations in the vWF gene has been difficult due to the complexity and large size of the locus. This problem has been circumvented in part due to the advent of primers specific for the gene sequence and the polymerase chain reaction (PCR). In 1993 Ginsburg and Sadler presented a concise summary of the different types of von Willebrand disease and their respective mutations. Their study revealed that with two exceptions, mutations causing the type II form of the disorder cluster in the 134 amino acid segment of the vWF A2 homologous repeat encoded by exon 28. Abnormal intracellular transport leading to a selective loss of the larger multimers and a significant decrease in vWF secretion can both be associated with type II vW disease. Within the gene encoding vWF there are mutational hot spots such as the dinucleotide CG which are particularly prone to mutations that drastically alter the phenotype. Such mutations may be linked to type III von Willebrand disease where particular lesions (including various nonsense mutations at codons 365, 896, and 1772) and numerous deletions- all of which by their nature adequately explain the severity of the type III phenotype exhibited. Considerable evidence also exist that emphasizes the role of Alu repeats within the von Willebrand Factor gene. These Alu repeats have been implicated in illegitimate recombination events leading to the duplication or deletion of the gene sequence.
To eliminate any confusion between factor VIII, the protein absent in hemophilia A, the von Willebrand factor gene was changed from its previous name- factor VIII related antigen. Today it is easy for many to confuse the symptoms of vWís disease with those of hemophilia A, an entirely separate bleeding disorder. A closer examination of the clinical manifestations of both diseases helps to distinguish each from the other. Whereas in hemophilia where bleeding takes place typically in muscles and joints, in von Willebrand disease bleeding occurs in epistaxis and mucous membranes. In addition, Menorrhagia, gastrointestinal bleeding and easing bruising are all indicative of the disorder. Specific tests for vW's disease include :bleeding time, factor VIII count, vWF antigen count, Ristocetin Cofactor Activity Test, vWF Multimers Test, and Platelet Function Tests. Unlike hemophilia A, the gene encoding von Willebrand factor is generally carried on one of the autosomes (non-sex chromosome) -chromosome 12- and therefore the disease occurs with equal frequency and severity in both sexes. However sex-linked forms of the disorder have been known to exist. Therefore, like hemophilia some forms of vW disease only have abnormal X chromosomes. And because the male has only one X chromosome he has no second normal X chromosome (as in females) to protect him from the related symptoms. Therefore the complexity of von Willebrandís disease includes specific mutations that only affect the male population.
Von Willebrand disease is in general a much less severe disease than hemophilia. And bleeding is usually the result of accidents or surgical operations. Further studies of the vWF gene, and its underlying structure will continue to shed some insight into the possible nature of the von Willebrand defect.

References
1. Cooper, David N. and Edward G.D. Tuddenham. The Molecular Genetics of Haemostasis and its Inherited Disorders. Oxford University Press:NY.1994.
2. Goodnight, Scott H. and William E. Hathway. Disorders of Hemostasis and Thrombosis. McGraw-Hill, Inc.:Toronto.1993
3. Kessler, Craig M. and Jeanne M. Lusher. Hemophilia and Von Willebrand Disease in the 1990's. Elsevier Science Publishers B. V.:NY.1991.
4. Messeih, Adel A. et al. Hematology Case Studies. Medical Examination Publishing Co.: NY.1984

Return Case Studies in Virtual Genetics 1996-1997