Molecular genetics of hemophilia A

Hemophilia A is an X-linked bleeding disorder resulting from a defect in coagulation factor VIII. Clinical severity, the level of factor VIII activity and coagulant antigen vary widely. However, the three parameters breed true in families, indicating that the phenotypic expression directly reflects the genetic defect. In about 5%, hemophilia A results from partial deletion of the factor VIII gene and is clinically severe. In another 5% single base mutations have been found, which destroy the binding sites for the restriction enzyme TaqI. They can be "nonsense" mutations resulting in stop codons and clinically severe hemophilia, or "missense" mutations resulting in amino acid changes and milder forms of hemophilia. By the use of the polymerase chain reaction and denaturing gradient gel electrophoresis we have detected several point mutations. The formation of anti-factor VIII antibodies appears to be more frequent in patients with defects resulting in absence of factor VIII protein. Carrier detection and prenatal diagnosis can be made with 100% certainty in families with identified mutations. In their absence, polymorphisms affecting recognition sequences for 2 restriction enzymes (BclI and XbaI) within or outside the factor VIII gene can serve as a tag for the mutation and be followed through the pedigree. In the absence of any informative polymorphism the conventional methods for carrier detection are still helpful.--In roughly 1/3 of the patients, the mutation appears "sporadic". However, it can usually be traced within one or two generations of the proband. --Some patients have mosaicism for sporadic mutations, indicating that mutagenesis not necessarily occurs at the level of the gametes.(ABSTRACT TRUNCATED AT 250 WORDS)