Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Jun;87(12):4421–4425. doi: 10.1073/pnas.87.12.4421

Structural and functional basis of the developmental regulation of human coagulation factor IX gene: factor IX Leyden.

S Hirosawa 1, J B Fahner 1, J P Salier 1, C T Wu 1, E W Lovrien 1, K Kurachi 1
PMCID: PMC54126  PMID: 2352926

Abstract

Hemophilia B Leyden is characterized by unusual developmental regulation of factor IX synthesis in affected individuals. One family affected with the hemophilia B Leyden phenotype was found to have a specific single-base mutation (G----A) at nucleotide -6 of the factor IX gene. The mutation site was found in a small region of the 5'-untranslated sequence designated the Leyden-specific region (LS region). This region, approximately 40 base pairs in length, contains the unique mutation sites of all the known factor IX Leyden genes (five families) analyzed to date. This fact strongly suggests that the LS region is directly or indirectly involved in the developmental regulation of factor IX biosynthesis. Base changes at nucleotide -20 as well as at nucleotide -6 and deletions of the 3' half of the LS region reduced expression activity of the factor IX gene to approximately 15-31% that of the normal control, as assessed in a cultured cell (HepG2) expression system. The LS region binds at least two proteins. Androgen significantly increased the transcriptional activities of both mutant and normal factor IX genes in a concentration-dependent manner.

Full text

PDF
4421

Images in this article

4423Image
on p.4423
4424Image
on p.4424

Selected References

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

  1. Berkhout B., Silverman R. H., Jeang K. T. Tat trans-activates the human immunodeficiency virus through a nascent RNA target. Cell. 1989 Oct 20;59(2):273–282. doi: 10.1016/0092-8674(89)90289-4. [DOI] [PubMed] [Google Scholar]
  2. Beverley D. W., Inwood M. J., Chance G. W., Schaus M., O'Keefe B. 'Normal' haemostasis parameters: a study in a well-defined inborn population of preterm infants. Early Hum Dev. 1984 Apr;9(3):249–257. doi: 10.1016/0378-3782(84)90035-5. [DOI] [PubMed] [Google Scholar]
  3. Briët E., Bertina R. M., van Tilburg N. H., Veltkamp J. J. Hemophilia B Leyden: a sex-linked hereditary disorder that improves after puberty. N Engl J Med. 1982 Apr 1;306(13):788–790. doi: 10.1056/NEJM198204013061306. [DOI] [PubMed] [Google Scholar]
  4. Briët E., Wijnands M. C., Veltkamp J. J. The prophylactic treatment of hemophilia B Leyden with anabolic steroids. Ann Intern Med. 1985 Aug;103(2):225–226. doi: 10.7326/0003-4819-103-2-225. [DOI] [PubMed] [Google Scholar]
  5. Camper S. A., Godbout R., Tilghman S. M. The developmental regulation of albumin and alpha-fetoprotein gene expression. Prog Nucleic Acid Res Mol Biol. 1989;36:131–143. doi: 10.1016/s0079-6603(08)60167-1. [DOI] [PubMed] [Google Scholar]
  6. Chang C. S., Kokontis J., Liao S. T. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988 Apr 15;240(4850):324–326. doi: 10.1126/science.3353726. [DOI] [PubMed] [Google Scholar]
  7. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Forestier F., Daffos F., Rainaut M., Solé Y., Amiral J. Vitamin K dependent proteins in fetal hemostasis at mid trimester of pregnancy. Thromb Haemost. 1985 Jun 24;53(3):401–403. [PubMed] [Google Scholar]
  9. Fried M., Crothers D. M. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis. Nucleic Acids Res. 1981 Dec 11;9(23):6505–6525. doi: 10.1093/nar/9.23.6505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garewal H. S., Corrigan J. J., Jr, Durie B. G., Jeter M. A., Damiano M. L. Effect of danazol on coagulation parameters and bleeding in hemophilia. JAMA. 1985 Feb 22;253(8):1154–1156. [PubMed] [Google Scholar]
  11. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gralnick H. R., Maisonneuve P., Sultan Y., Rick M. E. Benefits of danazol treatment in patients with hemophilia A (classic hemophilia). JAMA. 1985 Feb 22;253(8):1151–1153. [PubMed] [Google Scholar]
  13. Gralnick H. R., Rick M. E. Danazol increases factor VIII and factor IX in classic hemophilia and Christmas disease. N Engl J Med. 1983 Jun 9;308(23):1393–1395. doi: 10.1056/NEJM198306093082305. [DOI] [PubMed] [Google Scholar]
  14. Ham J., Thomson A., Needham M., Webb P., Parker M. Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus. Nucleic Acids Res. 1988 Jun 24;16(12):5263–5276. doi: 10.1093/nar/16.12.5263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Johnson P. F., McKnight S. L. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. doi: 10.1146/annurev.bi.58.070189.004055. [DOI] [PubMed] [Google Scholar]
  16. Koeberl D. D., Bottema C. D., Buerstedde J. M., Sommer S. S. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG. Am J Hum Genet. 1989 Sep;45(3):448–457. [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Kunkel T. A., Roberts J. D., Zakour R. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. doi: 10.1016/0076-6879(87)54085-x. [DOI] [PubMed] [Google Scholar]
  19. Laspia M. F., Rice A. P., Mathews M. B. HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation. Cell. 1989 Oct 20;59(2):283–292. doi: 10.1016/0092-8674(89)90290-0. [DOI] [PubMed] [Google Scholar]
  20. Mandalaki T., Louizou C., Dimitriadou C., Briët E. Haemophilia B Leyden in Greece. Thromb Haemost. 1986 Dec 15;56(3):340–342. [PubMed] [Google Scholar]
  21. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Reitsma P. H., Mandalaki T., Kasper C. K., Bertina R. M., Briët E. Two novel point mutations correlate with an altered developmental expression of blood coagulation factor IX (hemophilia B Leyden phenotype). Blood. 1989 Feb 15;73(3):743–746. [PubMed] [Google Scholar]
  23. Rouault T. A., Hentze M. W., Caughman S. W., Harford J. B., Klausner R. D. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science. 1988 Sep 2;241(4870):1207–1210. doi: 10.1126/science.3413484. [DOI] [PubMed] [Google Scholar]
  24. Salier J. P., Kurachi K. A CAT expression vector with virtually no background: pUMSVOCAT. Biotechniques. 1989 Jan;7(1):30–31. [PubMed] [Google Scholar]
  25. Terwiel J. P., Veltkamp J. J., Bertina R. M., van der Linden I. K., van Tilburg N. H. Coagulation factors in the premature infant born after about 32 weeks of gestation. Biol Neonate. 1985;47(1):9–18. doi: 10.1159/000242085. [DOI] [PubMed] [Google Scholar]
  26. Yoshitake S., Schach B. G., Foster D. C., Davie E. W., Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985 Jul 2;24(14):3736–3750. doi: 10.1021/bi00335a049. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES