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Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A

Nature Genetics volume 5, pages 236–241 (1993)Cite this article

Abstract

Mutations in the factor VIII gene have been discovered for barely more than half of the examined cases of severe haemophilia A. To account for the unidentified mutations, we propose a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. We present evidence to support this model and describe a Southern blot assay that detects the inversion. These findings should be valuable for genetic prediction of haemophilia A in ∼45% of families with severe disease.

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References

  1. Verkerk, A.J.M.H. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    Article  CAS  Google Scholar 

  2. Kunkel, L.M. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 322, 73–77 (1986).

    Article  CAS  Google Scholar 

  3. Tuddenham, E.G.D. et al. Haemophilia A: Database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucl. Acids Res. 19, 4821–4833 (1991).

    Article  CAS  Google Scholar 

  4. Higuchi, M. et al. Molecular characterization of mild-to-moderate hemophilia A: Detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc. natn. Acad. Sci. U.S.A. 88, 8307–8311 (1991).

    Article  CAS  Google Scholar 

  5. Higuchi, M. et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc. natn. Acad. Sci. U.S.A. 88, 7405–7409 (1991).

    Article  CAS  Google Scholar 

  6. Naylor, J.A., Green, P.M., Rizza, C.R. & Giannelli, F. Analysis of factor VIII mRNA defects in everyone of 28 haemophilia A patients. Hum. molec. Genet. 2, 11–17 (1993).

    Article  CAS  Google Scholar 

  7. Gitschier, J. et al. Characterization of the human factor VIII gene. Nature 312, 326–330 (1984).

    Article  CAS  Google Scholar 

  8. Levinson, B., Kenwrick, S., Lakich, D., Hammonds, G. & Gitschier, J. A transcribed gene in an intron of the human factor VIM gene. Genomics 7, 1–11 (1990).

    Article  CAS  Google Scholar 

  9. Levinson, B., Kenwrick, S., Gamel, P., Fisher, K. & Gitschier, J. Evidence for a third transcript from the human factor VIII gene. Genomics 14, 585–589 (1992).

    Article  CAS  Google Scholar 

  10. Freije, D. & Schlessinger, D. A 1.6-Mb contig of yeast artificial chromosomes around the human factor VIII gene reveals three regions homologous to probes for the DXS115 locus and two for the DXYS64 locus. Am. J. hum. Genet. 51, 66–80 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Patterson, M. et al. An intronic region within the human factor VIM gene is duplicated within Xq28 and is homologous to the polymorphic locus DXS115 (767). Am. J. hum. Genet. 44, 679–685 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Smithies, O. Chromosomal rearrangements and protein structure. Cold Spring Harb. Symp. Quant. Biol. 29, 309–319 (1964).

    Article  CAS  Google Scholar 

  13. Efremov, G.D. Hemoglobins Lepore and anti-Lepore. Hemoglobin 2, 197–233 (1978).

    Article  CAS  Google Scholar 

  14. Yen, P.H. et al. Frequent deletions of the human X chromosome distal short arm result from recombination between low copy repetitive elements. Cell 61, 603–610 (1990).

    Article  CAS  Google Scholar 

  15. Pentao, L., Wise, C.A., Chinault, A.C., Patel, P.I. & Lupski, J.R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet. 2, 292–300 (1992).

    Article  CAS  Google Scholar 

  16. Jones, R.W., Old, J.M., Trent, R.J., Clegg, J.B. & Weatherall, D.J. Major rearrangement in the human β-globin gene cluster. Nature 291, 39–44 (1981).

    Article  CAS  Google Scholar 

  17. Karathanasis, S.K., Ferris, E. & Haddad, I.A. DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis. Proc. natn. Acad. Sci. U.S.A. 84, 7198–7202 (1987).

    Article  CAS  Google Scholar 

  18. Kulozik, A.E., Bellan-Koch, A., Kohne, E. & Kleihauer, E. A deletion/inversion rearrangement of the β-globin gene cluster in a Turkish family with λβo-Thalassemia Intermedia. Blood 79, 2455–2459 (1992).

    CAS  PubMed  Google Scholar 

  19. Rizza, C.R. & Spooner, R.J.D. Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976–1980: report on behalf of the directors of haemophilia centres in the United Kingdom. Brit Med. J. 286, 929–933 (1983).

    Article  CAS  Google Scholar 

  20. Katz, B.Z., Raab-Traub, N. & Miller, G. Latent and replicating forms of Epstein-Barr virus DNA in lymphomas and lymphoproliferative disease. J. inf. Dis. 160, 589–598 (1989).

    Article  CAS  Google Scholar 

  21. Kenwrick, S. & Gitschier, J. A contiguous, 3-Mb physical map of Xq28 extending from the color-blindness locus to DXS15. Am. J. hum. Genet. 45, 873–882 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Carle, G.F. & Olson, M.V. An electrophoretic karyotype for yeast. Proc. natn. Acad. Sci. U.S.A. 82, 3756–3760 (1985).

    Article  CAS  Google Scholar 

  23. Church, G. & Gilbert, W. Genomic sequencing. Proc. natn. Acad. Sci. U.S.A. 81, 1991–1995 (1984).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Medicine, University of California, San Francisco, California, 94143-0724, USA

    Delia Lakich & Jane Gitschier

  2. Center for Medical Genetics and Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA

    Haig H. Kazazian Jr. & Stylianos E. Antonarakis

  3. Department of Genetics, University of Geneva Medical School, Geneva, Switzerland

    Stylianos E. Antonarakis

Authors
  1. Delia Lakich
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  2. Haig H. Kazazian Jr.
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  3. Stylianos E. Antonarakis
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  4. Jane Gitschier
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Lakich, D., Kazazian, H., Antonarakis, S. et al. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 5, 236–241 (1993). https://doi.org/10.1038/ng1193-236

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