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Blood, 15 January 2004, Vol. 103, No. 2, pp. 586-593. Prepublished online as a Blood First Edition Paper on September 22, 2003; DOI 10.1182/blood-2003-02-0419. This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2003-02-0419v1 103/2/586    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by von Ahsen, N. Articles by Oellerich, M. Search for Related Content PubMed PubMed Citation Articles by von Ahsen, N. Articles by Oellerich, M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The intronic prothrombin 19911A>G polymorphism influences splicing efficiency and modulates effects of the 20210G>A polymorphism on mRNA amount and expression in a stable reporter gene assay system Nicolas von Ahsen, and Michael Oellerich From the Department of Clinical Chemistry, Georg-August University, Göttingen, Germany. The common prothrombin gene cleavage site mutation 20210G>A is associated with elevated prothrombin levels and thrombosis. The pathomechanism of the 20210G>A mutation was explained by increased mRNA formation and/or more efficient translation. Human studies also showed an influence of the intronic 19911A>G polymorphism on prothrombin activity. We established HepG2 cell lines stably transfected with prothrombin mini-genes containing the last 2 prothrombin exons, the last intron, 3' untranslated region (UTR), and flanking sequence. The highest mRNA expression and protein activity resulted from the mutant haplotype 19911A-20210A. Haplotypes with wild-type cleavage site (19911A-20210G, 19911G-20210G) also differed significantly as a consequence of the intronic 19911 mutation; the 19911G-20210G haplotype showed lower expression than the 19911A-20210G haplotype, whereas previous clinical studies have reported elevated prothrombin activity with the 19911G-20210G haplotype. The cleavage site pattern was homogeneous with 20210A, which may cause a favorable intracellular processing, and heterogeneous with 20210G. In an independent assay for splicing efficiency, 19911G showed about 30% higher efficiency than 19911A. We conclude that the intronic 19911A>G single nucleotide polymorphism is itself functional and changes splicing efficiency by altering a known functional pentamer motif. Further studies are needed to define the value of additional prothrombin 19911 genotyping for thrombophilia screening, especially in cases heterozygous for 20210G>A. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Is the prothrombin 19911A>G polymorphism a functional noncoding variant? Haidy H. A. G. M. van der Putten, Rogier M. Bertina, Hans L. Vos, Nicolas von Ahsen, and Michael Oellerich Blood 2005 105: 2995-2996. [Full Text] [PDF] This article has been cited by other articles: M. Siedlinski, C. C. van Diemen, D. S. Postma, J. M. Vonk, and H. M. Boezen Superoxide dismutases, lung function and bronchial responsiveness in a general population Eur. Respir. J., May 1, 2009; 33(5): 986 - 992. [Abstract] [Full Text] [PDF] M. E. Sarasquete, R. 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Medcalf The relationship between the prothrombin upstream sequence element and the G20210A polymorphism: the influence of a competitive environment for mRNA 3'-end formation Nucleic Acids Res., February 17, 2005; 33(3): 1010 - 1020. [Abstract] [Full Text] [PDF] F. R. Rosendaal Venous Thrombosis: The Role of Genes, Environment, and Behavior Hematology, January 1, 2005; 2005(1): 1 - 12. [Abstract] [Full Text] [PDF] T. Heller, M. Oellerich, V. W. Armstrong, and N. von Ahsen Rapid Detection of ITPA 94C>A and IVS2 + 21A>C Gene Mutations by Real-Time Fluorescence PCR and in Vitro Demonstration of Effect of ITPA IVS2 + 21A>C Polymorphism on Splicing Efficiency Clin. Chem., November 1, 2004; 50(11): 2182 - 2184. [Full Text] [PDF] N. von Ahsen, V. W. Armstrong, and M. Oellerich Rapid, Long-Range Molecular Haplotyping of Thiopurine S-Methyltransferase (TPMT*) *3A, *3B, and *3C Clin. Chem., September 1, 2004; 50(9): 1528 - 1534. [Abstract] [Full Text] [PDF] S. Danckwardt, N. H. Gehring, G. Neu-Yilik, P. Hundsdoerfer, M. Pforsich, U. Frede, M. W. Hentze, and A. E. Kulozik The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations Blood, July 15, 2004; 104(2): 428 - 435. [Abstract] [Full Text] [PDF]

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