Molecular basis of haemophilia A.
Technologies in molecular biology have greatly advanced the knowledge regarding the origin of haemophilia A and the physiology of the factor VIII (FVIII) protein. A variety of different mutations in the FVIII gene have been identified and their effects on the FVIII protein described. It has been shown that the frequency of haemophilia A is due to a high mutation rate predominantly in male germ cells. A significant proportion is originating de novo in early embryogenesis from somatic mutations, a finding that has implications for genetic counselling. The life-cycle of the FVIII protein and its structure-function relationships are continuously clarified. Most recently it has been shown that FVIII clearance from the circulation is mediated by the low-density lipoprotein receptor-related protein (LRP) and cell-surface heparan sulphate proteoglycans (HSPGs). These findings raise hope for novel recombinant FVIII molecules with prolonged half-life that may improve therapies for haemophlia A.
Oldenburg
J
J
Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donation Service, Baden, Württemberg-Hessen, D-60528 Frankfurt, Germany. joldenburg@bsdhessen.de
Ananyeva
N M
NM
Saenko
E L
EL
D005164:Factor IX / Q000235:genetics; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008297:Male; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000235:genetics
D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011973:Receptors, LDL; D014841:von Willebrand Factor; D005169:Factor VIII; D005164:Factor IX