Sunday, April 08, 2007
Genes for Hemophilia A & B and von Willebrand disease
The roles of Factor VIII and Factor IX in blood clotting are described in a recent posting [Blood Clotting: Intrinsic Activity]. Defects in the gene for Factor VIII cause a bleeding disorder called hemophilia A [OMIM 306700]. The gene is called F8 and it's located on the X chromosome at q28. The fact that it's X-linked means that males are more likely to be affected than females since females would have to be homozygous for the recessive allele. Heterozygous females are unaffected.
Deficiencies in Factor IX are caused by mutations in the F9 gene, which is also located on the X chromosome (q27.1-q27.2). The disease is called hemophilia B or Christmas disease. Factor IX used to be called Christmas factor after Stephen Christmas (1947-1993), the first patient with a known defect in this clotting factor [OMIM 306900]. It took some time, and a considerable amount of effort, to determine that there were two different genes on the X chromosome and hemophilia A was a different disease than hemophilia B.
The disease nomenclature is complicated by the fact that defects in the gene for von Willebrand Factor (vWF) are sometimes called hemophilia B. The correct name is von Willebrand disease. Recall that von Willebrand Factor associates with and stabilizes Factor VIII. Deficiencies of vWF are phenotypically equivalent to deficiencies in Factor VIII [OMIM 193400]. The gene for von Willibrand Factor is VWF and it's located at 12p13.3. The fact that it's autosomal means that the disease is not sex-linked.
Several of the VWF alleles confer a dominant phenotype. This is sometimes due to an insufficiently in the amount of von Willebrand Factor in blood plasma. The genetic term is haplo-insufficiency. It means that two functional alleles, one on each chromosome, are necessary in order to supply a sufficient amount of protein.