Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
권호 표지

Genetic Risk Factors of Hemophilia A

혈우병 A의 발병에 관여하는 유전적 요인

  • Shim, Ye-Jee (Department of Pediatrics, Kyungpook National University School of Medicine) ;
  • Lee, Kun-Soo (Department of Pediatrics, Kyungpook National University School of Medicine)
  • 심예지 (경북대학교 의과대학 소아과학교실) ;
  • 이건수 (경북대학교 의과대학 소아과학교실)
  • Received : 2010.06.06
  • Accepted : 2010.06.25
  • Published : 2010.03.01
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Abstract

Hemophilia A is a sex-linked recessive coagulation disorder associated with diverse mutations of the factor VIII gene and a variety of phenotypes. The type of mutation involved dictates the activity of factor VIII, and in turn the severity of bleeding episodes and development of alloantibodies against factor VIII (inhibitors). Missense mutations are the most common genetic risk factors for hemophilia A, especially mild to moderate cases, but carry the lowest risk for inhibitor development. On the other hand, intron 22 inversion is the most common mutation associated with severe hemophilia A and is associated with high risk of inhibitor formation. Large deletions and nonsense mutations are also associated with high risk of inhibitor development. Additional mutations associated with hemophilia A include frameshift and splice site mutations. It is therefore valuable to assess the mutational backgrounds of hemophilia A patients in order to to interpret their symptoms and manage their health problems.

Keywords

References

  1. O'Mahoney B. Global haemophilia care challenge and opportunities: World Federation of Haemophilia, 2002: Available form: http://www.wfh.org/2/docs/Programs/ Plenary2002_final.pdf.
  2. White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85:560.
  3. Lanzkowsky P. Manual of pediatric hematology and oncology. 4th ed. Elsevier academic press, 2005;312.
  4. Ehrenforth S, Kreuz W, Linde R, Funk M, Gungor T, Krackhardt B, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992;71:594-8.
  5. Haldane JBS. The rate of spontaneous mutation of a human gene. J Genetics 1935;31:317. https://doi.org/10.1007/BF02982403
  6. Gitschier J, Wood WI, Goralka YM, Wion KL, Chen EY, Eaton DH, et al. Characterization of the human factor VIII gene. Nature 1984;312:326-30. https://doi.org/10.1038/312326a0
  7. Levinson B, Kenwrick S, Lakich D, Hammonds G Jr, Gitschier J. A transcribed gene in an intron of the human factor VIII gene. Genomics 1990;7:1-11. https://doi.org/10.1016/0888-7543(90)90512-S
  8. Levinson B, Bermingham JR Jr, Metzenberg A, Kenwrick S, Chapman V, Gitschier J. Sequence of the human factor VIII-associated gene is conserved in mouse. Genomics 1992;13:862-5. https://doi.org/10.1016/0888-7543(92)90170-W
  9. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312:342-7. https://doi.org/10.1038/312342a0
  10. Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998;92:3983-96.
  11. Mannucci PM, Tuddenham EG. The hemophilias-from royal genes to gene therapy. N Engl J Med 2001;344: 1773-9. https://doi.org/10.1056/NEJM200106073442307
  12. Vehar GA, Keyt B, Eaton D, Rodriguez H, O'Brien DP, Rotblat F, et al. Structure of human factor VIII. Nature 1984;312:337-42. https://doi.org/10.1038/312337a0
  13. Lollar P, Knutson GJ, Fass DN. Activation of porcine factor VIII:C by thrombin and factor Xa. Biochemistry 1985;24:8056-64. https://doi.org/10.1021/bi00348a033
  14. Vlot AJ, Koppelman SJ, Bouma BN, Sixma JJ. Factor VIII and von Willebrand factor. Thromb Haemostat 1998;79:455-65.
  15. Kaufman RJ, Pipe SW. Regulation of VIII expression and activity by von Willebrand factor. Thromb Haemostat 1999;82:201-8.
  16. Weiss HJ, Sussman II, Hoyer LW. Stabilization of Factor VIII in Plasma by the von Willebrand Factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease. J Clin Invest 1977;60:390-404. https://doi.org/10.1172/JCI108788
  17. Saenko EL, Shima M, Sarafanov AG. Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. Trends Cardiovasc Med 1999;9:185-92. https://doi.org/10.1016/S1050-1738(00)00019-0
  18. Saenko EL, Ananyeva NM, Tuddenham EG, Kemball-Cook G. Factor VIII-novel insights into form and function. Br J Haematol 2002;119:323-31. https://doi.org/10.1046/j.1365-2141.2002.03793.x
  19. Van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phopholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem 1981;256:3433-42
  20. Lakich D, Kazazian HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Getet 1993; 5:236-41. https://doi.org/10.1038/ng1193-236
  21. Naylor J, Brinke A, Hassock S, Green PM, Giannelli F. Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Hum Mol Genet 1993;2:1773-8. https://doi.org/10.1093/hmg/2.11.1773
  22. Naylor JA, Buck D, Green P, Williamson H, Bentley D, Gianneill F. Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum Mol Genet 1995;4:1217-24. https://doi.org/10.1093/hmg/4.7.1217
  23. Oldenburg J, Ananyeva NM, Saenko EL. Molecular basis of haemophilia A. Haemophilia 2004;10:133-9. https://doi.org/10.1111/j.1365-2516.2004.01005.x
  24. Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 2006;12: 15-22.
  25. Repesse Y, Slaoui M, Ferrandiz D, Gautier P, Costa C, Costa JM, et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost 2007;5:1469-76. https://doi.org/10.1111/j.1538-7836.2007.02591.x
  26. Millar DS, Kakkar VV, Cooper DN. Screening for inversions in the factor VIII (F8) gene causing severe haemophilia A. Blood Coagul Fibrinolysis 994;5:239-42. https://doi.org/10.1097/00001721-199404000-00013
  27. Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002;99:168-74. https://doi.org/10.1182/blood.V99.1.168
  28. Brinke A, Tagliavacca L, Naylor J, Green P, Giangrande P, Giannelli F. Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia. Hum Mol Genet 1996;5:1945-51. https://doi.org/10.1093/hmg/5.12.1945
  29. Youssoufian H, Antonarakis SE, Aronis S, Tsiftis G, Phillips DG, Kazazian JJ Jr. Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci USA 1987;84:3772-6. https://doi.org/10.1073/pnas.84.11.3772
  30. Bardoni B, Sampietro M, Romano M, Crapanzano M, Mannucci PM, Camerino G. Characterization of a partial delation of the factor VIII gene in a haemophiliac with inhibitor. Hum Genet 1988;79:86-8. https://doi.org/10.1007/BF00291718
  31. Salviato R, Belvini D, Are A, Radossi P, Tagariello G. Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs. Haemophilia 2002;8:17-21.
  32. Woods-Samuels P, Kazazian HH Jr, Antonarakis SE. Nonhomologous recombination in the human genome: deletions in the human factor VIII gene. Genomics 1991;10:94-101. https://doi.org/10.1016/0888-7543(91)90489-2
  33. Van de Water N, Williams R, Ockelford P, Browett P. A 20.7 kb deletion within the factor VIII gene associated with LINE-1 element insertion. Thromb Haemost 1998;79:938-42.
  34. Vidal F, Farssac E, Tusell J, Puig L, Gallardo D. First molecular characterization of an unequal homologous alu-mediated recombination event responsible for hemophilia. Thromb Haemost 2002;88:12-6.
  35. Rossetti LC, Goodeve A, Larripa IB, De Brasi CD. homeologous recombination between AluSx-sequences as a cause of hemophilia. Hum Mut 2004;24:440.
  36. Nakaya SM, Hsu TC, Geraghty SJ, Manco-Johnson MJ, Thomsom AR. Severe hemophilia A due to a 1.3 kb factor VIII gene deletion including exon 24: homologous recombination between 41 bp within an Alu repeat sequence in introns 23 and 24. J Thromb Haemost 2004;2:1941-5. https://doi.org/10.1111/j.1538-7836.2004.00963.x
  37. Sommer SS, Scaringe WA, Hill KA. Is Alu-mediated recombination an important cause of hemophilia? Thromb Haemost 2002;88:3-4.
  38. Cooper DN, Krawczak M. The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 1990; 85:55-74.
  39. Cooper DN, Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet 1988;78:151. https://doi.org/10.1007/BF00278187
  40. Youssoufian H, Kazazian HH Jr, Phillips DG, Aronis S, Tsiftis G, Brown VA, et al. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 1986;324:380-2. https://doi.org/10.1038/324380a0
  41. Antonarakis SE, Youssoufian H, Kazazian HH Jr. Molecular genetics of hemophilia A in man (factor VIII deficiency). Mol Biol Med 1987;4:81-94.
  42. Mikami S, Nishimura T, Naka H, Kuze K, Fukui H, Tone M, et al. Nonsense mutations in factor VIII gene of a severe haemophiliac patient with anti-factor VIII antibody. Jpn J Human Genet 1988;33:409-15. https://doi.org/10.1007/BF01897781
  43. Kemball-Cook G, Tuddenham EG, Wacey AI. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4. Nucleic Acids Res 1998;26: 216-9. Available form: http://hadb.org.uk https://doi.org/10.1093/nar/26.1.216
  44. Young M, Inaba H, Hoyer LW, Higuchi M, Kazazian HH Jr, Antonarakis SE. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet 1997;60:565-73.
  45. Kreuz W, Becker S, Lenz E, Martinez-Saguer I, Escuriola-Ettingshausen C, Funk M, et al. Factor VIII Inhibitors in Patients with Hemophilia A: Epidemiology of Inhibitor Development and Induction of Immune Tolerance for Factor VIII. Semin Thromb Haemost 1995;21:382-9. https://doi.org/10.1055/s-2007-1000659
  46. Scharrer I, Neutzling O. Incidence of inhibitors in haemophiliacs. A review of the literature. Blood Coagul Fibrinolysis 1993;4:753-8. https://doi.org/10.1097/00001721-199310000-00012
  47. Brettler DB. Inhibitors in congenital haemophilia. Baillieres Clin Haematol 1996;9:319-29. https://doi.org/10.1016/S0950-3536(96)80066-7
  48. Darby SC, Keeling DM, Spooner RJ, Wan Kan S, Giangrande PL, Collins PW, et al. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99. J Thrmb Haemost 2004;2:1047-54. https://doi.org/10.1046/j.1538-7836.2004.00710.x
  49. Oldenburg J, Schroder J, Brackmann HH, Muller-Reible C, Schwaab R, Tuddenham E. Environmental and genetic factors influencing inhibitors development. Semin Hematol 2004;41:82-8. https://doi.org/10.1053/j.seminhematol.2003.11.016
  50. Schwaab R, Brackmann HH, Meyer C, Seehafer J, Kirchgesser M, Haack A, et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995;74:1402-6.
  51. Bolton-Maggs PH, Pasi J. Haemophilia A and B. Lancet 2003;361:1801-9. https://doi.org/10.1016/S0140-6736(03)13405-8
  52. Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet 2005; 6:488-501. https://doi.org/10.1038/nrg1617