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Hemophilia A

Hemophilia A. Constructed by Sarah Akiki. Overview of the disease.

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Hemophilia A

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  1. Hemophilia A Constructed by Sarah Akiki

  2. Overview of the disease • Hemophilia A is an X-linked, recessive, bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. Affected individuals develop a variable phenotype of hemorrhage into joints and muscles, and prolonged bleeding from wounds. This phenotype is caused by heterogeneous in the factor VIII gene. • (It affects between 1 in 5000 to 1 in 10,000 males in most populations). • Replacement of factor VIII is done using a variety of preparations derived from human plasma or recombinant techniques. While replacement therapy is effective in most cases, 10 to 15% of treated individuals develop neutralizing antibodies that decrease its effectiveness.

  3. Clinical features / Phenotype • The severity and frequency of bleeding in hemophilia A is inversely related to the amount of residual factor VIII. The most effected parts of the body are the joints causing swelling, pain, decreased function, and degenerative arthritis. • Similarly, muscle hemorrhage can occur leading to necrosis. Hematuria would be present occasionally which is usually painless. • Bleeding from tongue or lip is persistent. • Prolonged bleeding from wounds.

  4. INTERESTING! • Rosendaal presented evidence supporting his earlier findings that mortality due to ischemic heart disease is lower in hemophilia patients than in the general male population.

  5. Genotype / Molecular genetics • In 1993, McGinniss reported that half of hemophilia A patients have no detectable facto VIII; about 5% have normal levels of dysfunctional factor VIII as protein and are termed CRM-+ whereas the rest ( 45%) have plasma factor VIII Ag protein reduced to an extent roughly comparable to the level of factor VIIIC activity and are designated CRM-reduced.

  6. Some genetics • Carrier females have a 50% chance of transmitting the F8 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers. Affected males transmit the mutation to all of their daughters and none of their sons.

  7. More statistics • In hemophilia A, the factor VIII clotting activity is usually lower than 35% with a normal, functional von Willebrand factor level. Classification of hemophilia A: • .Severe hemophilia A: <1% factor VIII clotting activity • .Moderately severe hemophilia A: 1-5% factor VIII clotting activity • .Mild hemophilia A: 6-35% factor VIII clotting activity

  8. Mutations and protein function • It’s been well known that point mutations in the factor VIII gene are responsible for most cases of hemophilia A and only a small proportion of these mutations can be recognized by restriction endonuclease analysis, PCR and denaturing gradient gel electrophoresis (DGGE) were used to characterize single nucleotide substitutions. • A GC clamp was attached to the 5-prime PCR primer to allow detection of most single base changes in DNA fragments ranging in size from 249 to 356 bp. (A 'GC clamp' is a sequence rich in G and C such that it is relatively resistant to melting by heating).

  9. Biochemistry • Hemophilia A is a complex of a large inert carrier protein and a noncovalently bound small fragment which contains the procoagulant active site. • The factor VIII complex, with a molecular weight in excess of 1 million, has 2 components: (1) factor VIII (molecular weight of 293,000 ) called factor VIII C, when measured by procoagulant activity and factor VIII Ag, when measured immunologically and (2) factor VIII R (the von Willebrand factor or vWF) has a molecular weight of 220,000. Polymerization leads to the high molecular weight of the factor VIII complex (Levin, 1979). Factor VIII is encoded by the factor VIII gene on Xq28.

  10. The C2 MUTATION DOMAIN • The crystal structure of the human factor VIII C2 domain at a resolution of 1.5 angstroms was reported in 1999. The structure of this protein shows a beta-sandwich core, from which 2 beta-turns and a loop display a group of solvent-exposed hydrophobic residues. Behind the hydrophobic surface lies a ring of positively charged residues. This motif suggests a mechanism for membrane binding involving both hydrophobic and electrostatic interactions. The structure explains, in part, mutations in the C2 region of factor VIII that lead to bleeding disorders in hemophilia A.

  11. Factor VIII C2 at 1.5 A (3-D protein)

  12. More on the C2 mutation • Sequence and secondary structure

  13. Allelic variants • .0001 HEMOPHILIA A [F8C, ARG2307TER] • HEMOPHILIA A [F8C, EX26DEL] • HEMOPHILIA A [F8C, ARG2147TER] • HEMOPHILIA A [F8C, NEW SPLICE DONOR, IVS4] • HEMOPHILIA A [F8C, GLU272GLY] • FACTOR VIII (OKAYAMA) [F8C, ARG372HIS] • HEMOPHILIA A [F8C, EX26DEL] • HEMOPHILIA A [F8C, 23-BP DEL, FS]

  14. Finally… • The gene for factor VIII is composed by 186 kb organized into 26 exons! It has been said that the majority of the mutations are point mutations. Due to the huge number of these mutations I have just shown an example (C2). However, all these mutations contribute to the alteration and dysfunctional factor VIII which leads to the aberrant phenotype of bleeding disorder. • Possible self-limited treatment:  Individuals with hemophilia A are treated with intravenous infusion of factor VIII concentrate to control bleeding episodes quickly (within one hour if possible) and to prevent pain, disability, and chronic joint disease.

  15. CONCLUSION

  16. References • http://www.rcsb.org/pdb/explore/sequence.do?structureId=1D7P • http://www.ncbi.nlm.nih.gov/pubMed, OMIM • Some Google search: www.hog.org (hemophilia A pictures).

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