|
|
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.
 Previous Article | Next Article 
Submitted August 28, 2003
Accepted March 25, 2004
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, Matthias W Hentze, and Andreas E Kulozik*
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; University of Heidelberg-EMBL Molecular Medicine Partnership Unit, Heidelberg, Germany
EMBL, Heidelberg, Germany; University of Heidelberg-EMBL Molecular Medicine Partnership Unit, Heidelberg, Germany
* Corresponding author; email: andreas.kulozik{at}med.uni-heidelberg.de.
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 physiological 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 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 be disturbed by clinically relevant gain-of-function mutations.
 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]
|
|
|
|
|
