Advertisement

Faktor VIII: Molekularbiologie

  • E. G. Tuddenham
  • D. N. Cooper

Zusammenfassung

Die Struktur und Sequenz des humanen Faktör-VIII-Gens (FVIII-Gens) wurde 1984 gleichzeitig von 2 verschiedenen Forschergruppen publiziert (Gitschier et al.; Toole et al). Beide Arbeitsgruppen benutzten als Ausgangsmaterial eine genomische cDNA-Bibliothek, die aus einer Zellinie mit tetraploidem Chromosomensatz — also einer Zelllinie mit 4 X-Chromosomen — gewonnen wurde. Aus dieser Bibliothek konnte mit Hilfe von Oligonukleotiden, die entsprechend der Sequenz bekannter FVIII-Peptidfragmente synthetisiert worden waren, ein FVIII-Gen in einer Größe von über 200 Kilobasen (kB) isoliert werden. Damit umfaßt das FVIII-Gen etwa 0,1% des gesamten X-Chromosoms.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Casarino L, Pecorara M, Mori PG et al. (1986) Molecular basis for hemophilia A in Italians. Riv Clin Lab 16:227Google Scholar
  2. Cooper DN, Smith BA, Cooke HJ et al. (1985) An estimate of unique DNA sequence heterozygosity in the human genome. Hum Genet 69:201–205PubMedCrossRefGoogle Scholar
  3. Exner T, Richard KA, Kronenberg H (1983) Measurement of factor VIIIC AG by immunoradiometric assay in human tissue extracts. Thromb Res 32:427PubMedCrossRefGoogle Scholar
  4. Friedmann T (1989) Progress toward human gene therapy. Science 224:1275–1281CrossRefGoogle Scholar
  5. Fukui H, Aronson DL (eds) (1991) Recombinant factor VIII. Proceedings of the first international symposium on recombinant factor VIII. Semin Hematol (Suppl) 28:2Google Scholar
  6. Gitschier J, Wood WI, Goralka TM et al. (1984) Characterization of the human factor VIII gene. Nature 312:326–330PubMedCrossRefGoogle Scholar
  7. Hassan HJ, Leonardi A, Chelucci C et al. (1990) Blood coagulation factors in human embryonic-fetal development: Preferential expression of the FVIII/tissue factor pathway. Blood 76:1158–1164PubMedGoogle Scholar
  8. Higuchi M, Antonarakis SE, Kasch L et al. (1991a) Towards complete characterization of mild-to-moderate hemophilia A: Detection of the molecular defect in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 88:8307–8311PubMedCrossRefGoogle Scholar
  9. Higuchi M, Kazazian HH, Kasch L et al. (1991b) Molecular characterization of severe haemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci USA 88:7405–7409PubMedCrossRefGoogle Scholar
  10. Kaufman RJ, Wasley LC, Dormer AJ (1988) Synthesis, processing and secretion of recombinant human factor VIII expressed in mammalian cells. J Biol Chem 263:6352–6362PubMedGoogle Scholar
  11. Meulien P, Faure T, Mischler F et al. (1988) A new recombinant procoagulant protein derived from the cDNA encoding human factor VIII. Protein Eng 2:301–306PubMedCrossRefGoogle Scholar
  12. Naylor JA, Green PM, Montandon AJ et al. (1991) Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene. Lancet 337:635–639PubMedCrossRefGoogle Scholar
  13. Pattinson JK, Millar DS, Grundy CB et al. (1990) The molecular genetic analysis of haemophilia A; a directed-search strategy for the detection of point mutations in the human factor VIII gene. Blood 76:2242–2248PubMedGoogle Scholar
  14. Pavirani A, Meulien P, Harrer H et al. (1987) Two independent domains of factor VIII co-expressed using recombinant vaccinia viruses have procoagulant activity. Biochem Biophys Res Commun 145:234–240PubMedCrossRefGoogle Scholar
  15. Schwartz C, Fitch N, Phelan MC et al. (1987) Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX is present. Human Genet 76:54–57CrossRefGoogle Scholar
  16. Schwartz RS, Abildgaard CF, Aledorf LM et al. (1990) Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 323:1800–1805PubMedCrossRefGoogle Scholar
  17. Stel HV, Kwast TH van der, Veerman ECI (1983) Detection of factor VIII/coagulant antigen in human liver tissue. Nature 303:530–532PubMedCrossRefGoogle Scholar
  18. Toole JJ, Knopf JL, Wozney JM et al. (1984) Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312:342–347PubMedCrossRefGoogle Scholar
  19. Truett MA, Blacher R, Burke RL et al. (1985) Characterization of the polypeptide composition of human factor VIII: C and the nucleotide sequence and expression of the human kidney cDNA. DNA 4:333–349PubMedCrossRefGoogle Scholar
  20. Tuddenham EGD, Cooper DN, Gitschier J et al. (1991) Haemophilia A: database of nucleotide substitutions, deletions, insertions and re-arrangements of the factor VIII gene. Nucleic Acids Res 19:4821–4833PubMedCrossRefGoogle Scholar
  21. Van de Pol H, Mignot G, Bilhoreau N et al. (1989) In vitro and in vivo studies of a biologically active genetically engineered factor VIII molecule. Thromb Haemost 62:205Google Scholar
  22. Vehar GA, Keyte B, Eaton D et al. (1984) Structure of human factor VIII. Nature 312:337–342PubMedCrossRefGoogle Scholar
  23. Wehnert M, Herrmann FH, Wulff K (1989) Partial deletions of factor VIII gene as molecular diagnostic markers in haemophilia A. Disease Markers 7:113–117PubMedGoogle Scholar
  24. Wood WI, Capon DJ, Simonsen CC et al. (1984) Expression of active human factor VIII from recombinant DNA clones. Nature 312:330–337PubMedCrossRefGoogle Scholar
  25. Youssoufian H, Antonarakis SE, Aronis S et al. (1987) Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci USA 84:3773–3776CrossRefGoogle Scholar
  26. Youssoufian H, Antonarakis SE, Bell W et al. (1988) Nonsense and missense mutations in hemophilia A: Estimate of the relative mutation rate at CpG dinucleotides. Am J Hum Genet 42:718–725PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • E. G. Tuddenham
  • D. N. Cooper

There are no affiliations available

Personalised recommendations