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Blood, 15 July 2004, Vol. 104, No. 2, pp. 428-435. Prepublished online as a Blood First Edition Paper on April 1, 2004; DOI 10.1182/blood-2003-08-2894. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2894v1 104/2/428    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 Danckwardt, S. Articles by Kulozik, A. E. Search for Related Content PubMed PubMed Citation Articles by Danckwardt, S. Articles by Kulozik, A. E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations Sven Danckwardt, Niels H. Gehring, Gabriele Neu-Yilik, Patrick Hundsdoerfer, Margit Pforsich, Ute Frede, Matthias W. Hentze, and Andreas E. Kulozik From the Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany; EMBL—University of Heidelberg Molecular Medicine Partnership Unit, Germany; and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. The functional analysis of the common prothrombin 20210 G>A(F2 20210*A) mutation has recently revealed gain of function of 3'end processing as a novel genetic mechanism predisposing to human disease. We now show that the physiologic G at the cleavage site at position 20210 is the functionally least efficient nucleotide to support 3'end processing but has evolved to be physiologically optimal. Furthermore, the F2 3'end processing signal is characterized by a weak downstream cleavage stimulating factor (CstF) binding site with a low uridine density, and the functional efficiency of F2 3'end processing can be enhanced by the introduction of additional uridine residues. The recently identified thrombosis-related mutation (F2 20221*T) within the CstF binding site up-regulates F2 3'end processing and prothrombin biosynthesis in vivo. F2 20221*T thus represents the first example of a likely pathologically relevant mutation of the putative CstF binding site in the 3'flanking sequence of a human gene. Finally, we show that the low-efficiency F2 cleavage and CstF binding sites are balanced by a stimulatory upstream uridine-rich element in the 3'UTR. The architecture of the F2 3'end processing signal is thus characterized by a delicate balance of positive and negative signals. This balance appears to be highly susceptible to being disturbed by clinically relevant gain-of-function mutations. (Blood. 2004;104:428-435) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. L. Sartini, H. Wang, W. Wang, C. F. Millette, and D. L. Kilpatrick Pre-Messenger RNA Cleavage Factor I (CFIm): Potential Role in Alternative Polyadenylation During Spermatogenesis Biol Reprod, March 1, 2008; 78(3): 472 - 482. [Abstract] [Full Text] [PDF] J. B. Kunz, G. Neu-Yilik, M. W. Hentze, A. E. Kulozik, and N. H. Gehring Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation RNA, June 1, 2006; 12(6): 1015 - 1022. [Abstract] [Full Text] [PDF] E. Lyon Discovering Rare Variants by Use of Melting Temperature Shifts Seen in Melting Curve Analysis Clin. Chem., August 1, 2005; 51(8): 1331 - 1332. [Full Text] [PDF] M. Sachchithananthan, S. J. Stasinopoulos, J. Wilusz, and R. L. 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]

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