Hemophilia

Hemophilia is the term used to describe uncontrolled bleeding, which may range from mild ) bleeding after surgery or significant trauma) to severe (spontaneous bleeding into joints, muscle, and internal organs). Most examples are attributable to one of the two classic inherited hemophilias: the sex-linked disorders hemophilia A and hemophilia B. The most common of these is hemophilia A, which is caused by mutations in the gene on the human X-chromosome coding for the blood coagulation cofactor molecule, factor VIII. Hemophilia B is caused by mutations to another X-chromosome-encoded gene, that for the zymogen of the blood coagulation serine proteinase factor IX. Less common congenital bleeding disorders are caused by mutations in the genes coding for other proteinase components of the blood coagulation system (factors VII, X, XI, and prothrombin), the cofactor molecule factor V, fibrinogen, and the serpin a₂-antiplasmin. Other causes of bleeding are due to defects in platelet aggregation caused by mutations in the genes coding for the integrin a_IIb b₃ (glycoprotein IIb-IIIa, the platelet-fibrinogen binding site), the cell adhesion molecule von Willebrand factor, or its platelet binding-site glycoprotein Ib-IX.

 The molecular basis of both hemophilia A and B has been studied extensively. Historically, bleeding defects have provided the basis for defining the reactions of the blood coagulation pathways and, more recently, elucidating of structure–function relationships in the coagulation factors. Hemophilias A and B have also been valuable models in the study of mutational mechanisms. All possible types of gene disruption have been detected, including point mutations, deletions, insertions, duplications, and inversions, and they can lead to either absence of the protein, reduced levels of protein, protein with reduced functional activity, or nonfunctional protein.

In various populations, the frequency of hemophilia A is 1 in 510 × 10³ male births. Over 80 point mutations in the factor VIII gene have been detected. Of these, 27 cause severe hemophilia and are mainly nonsense mutations, while 29 cause moderate to severe hemophilia and all are missense mutations. The most functionally interesting of the latter are those that lead to normal levels of protein but with severely reduced activity, that is, with reduced specific activity, which account for 5% of the total point mutations. These are all mutations of the Arg residue at the P1 position, immediately preceding the peptide bond to be cleaved, of the thrombin cleavage sites of factor VIII, and involve the hypermutable CpG dinucleotide (which is susceptible to 5-methylcytosine deamination).

 The frequency of hemophilia B is one-sixth that of hemophilia A. More than 300 point mutations have been detected, 40% of which lead to factor IX with reduced specific activity; these mutations affect all the domains of factor IX. The mutations that can be most readily rationalized in structure–function terms include those leading to abnormal post-translational modification of the Gla domain ) ie, generation of g-carboxyglutamic acid and b-hydroxyaspartic acid residues), mutation of the arginine residues at the proteolytic activation sites, and mutations affecting the active-site serine residue. Over half of these mutations are in CpG dinucleotides, with C → T or G → A transition mutations.