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Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots

Abstract

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII1. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations2. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors3. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes4–6. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.

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References

  1. Hougie, C. in Haematology 3rd edn (eds Williams, W. J., Beutler, E., Erslev, A. J. & Lichtman, M. A.) 1381–1399 (McGraw-Hill, New York, 1983).

    Google Scholar 

  2. Hagldane, J. B. S. J. Genet. 31, 317–326 (1935).

    Article  Google Scholar 

  3. Gill, F. M. in Factor VIII Inhibitors (ed. Hoyer, L. W.) 19–29 (Liss, New York, 1984).

    Google Scholar 

  4. Gitschier, J. et al. Nature 315, 427–430 (1985).

    Article  ADS  CAS  Google Scholar 

  5. Antonarakis, S. E. et al. New Engl. J. Med. 313, 842–848 (1985).

    Article  CAS  Google Scholar 

  6. Gitschier, J. et al. Science 232, 1415–1416 (1986).

    Article  ADS  CAS  Google Scholar 

  7. Gitschier, J. et al. Nature 312, 326–330 (1984).

    Article  ADS  CAS  Google Scholar 

  8. Wood, W. I. et al. Nature 312, 330–337 (1984).

    Article  ADS  CAS  Google Scholar 

  9. Vehar, G. A. et al. Nature 312, 337–342 (1984).

    Article  ADS  CAS  Google Scholar 

  10. Toole, J. J. et al. Nature 312, 342–347 (1984).

    Article  ADS  CAS  Google Scholar 

  11. Wallace, R. B. et al. Nucleic Acids Res. 9, 3647–3656 (1981).

    Article  CAS  Google Scholar 

  12. Studencki, A. B. & Wallace, R. B. DNA 3, 7–15 (1984).

    Article  CAS  Google Scholar 

  13. Antonarakis, S. E. et al. Lancet i, 1407–1409 (1985).

    Article  Google Scholar 

  14. Goodfellow, P. N., Davies, K. E. & Ropers, H. H. Cytogenet. Cell Genet. 40, 296–352 (1985).

    Article  CAS  Google Scholar 

  15. Schumm, J. et al. Cytogenet. Cell Genet. 40, 739 (abstract) (1985).

    Google Scholar 

  16. Kazazian, H. H. Jr et al. Cytogenet. Cell Genet. 38 860 (1986).

    Google Scholar 

  17. Orkin, S. H. & Kazazian, H. H. Jr A. Rev. Genet. 18, 131–171 (1984).

    Article  CAS  Google Scholar 

  18. Chehab, F. F., Honig, G. R. & Kan, Y. W. Lancet i, 3–5 (1986).

    Article  Google Scholar 

  19. Nussinov, R. J. molec. Biol. 149, 125–131 (1981).

    Article  CAS  Google Scholar 

  20. Salser, W. Cold Spring Harb. Symp. quant. Biol. 42, 985–1002 (1977).

    Article  Google Scholar 

  21. Bird, A. P. Nucleic Acids Res. 8, 1499–1504 (1980).

    Article  CAS  Google Scholar 

  22. Coulondre, C., Miller, J. H., Farabaugh, P. J. & Gilbert, W. Nature 274, 775–780 (1978).

    Article  ADS  CAS  Google Scholar 

  23. Barker, D., Schafer, M. & White, R. Cell 36, 131–138 (1984).

    Article  CAS  Google Scholar 

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Youssoufian, H., Kazazian, H., Phillips, D. et al. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324, 380–382 (1986). https://doi.org/10.1038/324380a0

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