Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1990 Jan;46(1):53–62.

Molecular analysis of hemophilia A mutations in the Finnish population.

B Levinson 1, A E Lehesjoki 1, A de la Chapelle 1, J Gitschier 1
PMCID: PMC1683555  PMID: 2104741

Abstract

We have examined the Finnish hemophilia A population for factor VIII gene mutations. This study included 83 unrelated patients and revealed 10 mutations associated with hemophilia. Using cloned cDNA, genomic, and oligonucleotide probes, we have identified three classes of mutations: five mutations causing the loss of TaqI restriction sites, a point mutation resulting in a new TaqI site, and four partial gene deletions. Although exons 5 and 6 were involved in three of the four partial gene deletions, the extent of the DNA lost differs in each case. The fourth deletion was located entirely within intron 1 and segregated with the disease in a large hemophilia pedigree. There was no history of hemophilia in eight of the 10 families. The origin of the mutation was determined in six of these pedigrees, two of which showed evidence for maternal mosaicism.

Full text

PDF
60

Images in this article

56p56-a
on p.56
57Figure 1
on p.57
58Figure 2
on p.58
59Figure 3
on p.59
60Figure 4
on p.60

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E., Waber P. G., Kittur S. D., Patel A. S., Kazazian H. H., Jr, Mellis M. A., Counts R. B., Stamatoyannopoulos G., Bowie E. J., Fass D. N. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med. 1985 Oct 3;313(14):842–848. doi: 10.1056/NEJM198510033131402. [DOI] [PubMed] [Google Scholar]
  2. Bakker E., Van Broeckhoven C., Bonten E. J., van de Vooren M. J., Veenema H., Van Hul W., Van Ommen G. J., Vandenberghe A., Pearson P. L. Germline mosaicism and Duchenne muscular dystrophy mutations. Nature. 1987 Oct 8;329(6139):554–556. doi: 10.1038/329554a0. [DOI] [PubMed] [Google Scholar]
  3. Darras B. T., Francke U. A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male. Nature. 1987 Oct 8;329(6139):556–558. doi: 10.1038/329556a0. [DOI] [PubMed] [Google Scholar]
  4. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  5. Gitschier J., Kogan S., Levinson B., Tuddenham E. G. Mutations of factor VIII cleavage sites in hemophilia A. Blood. 1988 Sep;72(3):1022–1028. [PubMed] [Google Scholar]
  6. Gitschier J., Levinson B., Lehesjoki A. E., De La Chapelle A. Mosaicism and sporadic haemophilia: implications for carrier determination. Lancet. 1989 Feb 4;1(8632):273–274. doi: 10.1016/s0140-6736(89)91279-8. [DOI] [PubMed] [Google Scholar]
  7. Gitschier J. Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum Genet. 1988 Sep;43(3):274–279. [PMC free article] [PubMed] [Google Scholar]
  8. Gitschier J., Wood W. I., Goralka T. M., Wion K. L., Chen E. Y., Eaton D. H., Vehar G. A., Capon D. J., Lawn R. M. Characterization of the human factor VIII gene. Nature. 1984 Nov 22;312(5992):326–330. doi: 10.1038/312326a0. [DOI] [PubMed] [Google Scholar]
  9. Gitschier J., Wood W. I., Tuddenham E. G., Shuman M. A., Goralka T. M., Chen E. Y., Lawn R. M. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. 1985 May 30-Jun 5Nature. 315(6018):427–430. doi: 10.1038/315427a0. [DOI] [PubMed] [Google Scholar]
  10. HARDISTY R. M., MACPHERSON J. C. A one-stage factor VIII (antihaemophilic globulin) assay and its use on venous and capillary plasma. Thromb Diath Haemorrh. 1962 May 15;7:215–228. [PubMed] [Google Scholar]
  11. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  12. Higuchi M., Kochhan L., Olek K. A somatic mosaic for haemophilia A detected at the DNA level. Mol Biol Med. 1988 Feb;5(1):23–27. [PubMed] [Google Scholar]
  13. Kogan S. C., Doherty M., Gitschier J. An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med. 1987 Oct 15;317(16):985–990. doi: 10.1056/NEJM198710153171603. [DOI] [PubMed] [Google Scholar]
  14. Kunkel L. M., Smith K. D., Boyer S. H., Borgaonkar D. S., Wachtel S. S., Miller O. J., Breg W. R., Jones H. W., Jr, Rary J. M. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. doi: 10.1073/pnas.74.3.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lanman J. T., Jr, Pericak-Vance M. A., Bartlett R. J., Chen J. C., Yamaoka L., Koh J., Speer M. C., Hung W. Y., Roses A. D. Familial inheritance of a DXS164 deletion mutation from a heterozygous female. Am J Hum Genet. 1987 Aug;41(2):138–144. [PMC free article] [PubMed] [Google Scholar]
  16. Letter: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh. 1975 Dec 15;34(3):869–872. [PubMed] [Google Scholar]
  17. Levinson B., Janco R., Phillips J., 3rd, Gitschier J. A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences. Nucleic Acids Res. 1987 Dec 10;15(23):9797–9805. doi: 10.1093/nar/15.23.9797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maddalena A., Sosnoski D. M., Berry G. T., Nussbaum R. L. Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency. N Engl J Med. 1988 Oct 13;319(15):999–1003. doi: 10.1056/NEJM198810133191507. [DOI] [PubMed] [Google Scholar]
  19. Nevanlinna H. R. The Finnish population structure. A genetic and genealogical study. Hereditas. 1972;71(2):195–236. doi: 10.1111/j.1601-5223.1972.tb01021.x. [DOI] [PubMed] [Google Scholar]
  20. Page D. C., de la Chapelle A. The parental origin of X chromosomes in XX males determined using restriction fragment length polymorphisms. Am J Hum Genet. 1984 May;36(3):565–575. [PMC free article] [PubMed] [Google Scholar]
  21. Rossouw C. M., Vergeer W. P., du Plooy S. J., Bernard M. P., Ramirez F., de Wet W. J. DNA sequences in the first intron of the human pro-alpha 1(I) collagen gene enhance transcription. J Biol Chem. 1987 Nov 5;262(31):15151–15157. [PubMed] [Google Scholar]
  22. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  23. Wong C., Dowling C. E., Saiki R. K., Higuchi R. G., Erlich H. A., Kazazian H. H., Jr Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. 1987 Nov 26-Dec 2Nature. 330(6146):384–386. doi: 10.1038/330384a0. [DOI] [PubMed] [Google Scholar]
  24. Wood W. I., Gitschier J., Lasky L. A., Lawn R. M. Base composition-independent hybridization in tetramethylammonium chloride: a method for oligonucleotide screening of highly complex gene libraries. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1585–1588. doi: 10.1073/pnas.82.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Youssoufian H., Antonarakis S. E., Aronis S., Tsiftis G., Phillips D. G., Kazazian H. H., Jr Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3772–3776. doi: 10.1073/pnas.84.11.3772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Youssoufian H., Antonarakis S. E., Bell W., Griffin A. M., Kazazian H. H., Jr Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet. 1988 May;42(5):718–725. [PMC free article] [PubMed] [Google Scholar]
  27. Youssoufian H., Kasper C. K., Phillips D. G., Kazazian H. H., Jr, Antonarakis S. E. Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A. Hum Genet. 1988 Oct;80(2):143–148. doi: 10.1007/BF00702857. [DOI] [PubMed] [Google Scholar]
  28. Youssoufian H., Kazazian H. H., Jr, Patel A., Aronis S., Tsiftis G., Hoyer L. W., Antonarakis S. E. Mild hemophilia A associated with a cryptic donor splice site mutation in intron 4 of the factor VIII gene. Genomics. 1988 Jan;2(1):32–36. doi: 10.1016/0888-7543(88)90106-1. [DOI] [PubMed] [Google Scholar]
  29. Youssoufian H., Kazazian H. H., Jr, Phillips D. G., Aronis S., Tsiftis G., Brown V. A., Antonarakis S. E. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. 1986 Nov 27-Dec 3Nature. 324(6095):380–382. doi: 10.1038/324380a0. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES