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
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