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Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia

Nature Genetics volume 28, pages 389–392 (2001)Cite this article

Abstract

The G→A mutation at position 20210 of the prothrombin or coagulation factor II gene (F2) represents a common genetic risk factor for the occurrence of thromboembolic events1,2,3. This mutation affects the 3′-terminal nucleotide of the 3′ untranslated region (UTR) of the mRNA and causes elevated prothrombin plasma concentrations1,2,3,4 by an unknown mechanism. Here, we show that the mutation does not affect the amount of pre-mRNA, the site of 3′ end cleavage or the length of the poly(A) tail of the mature mRNA. Rather, we demonstrate that the physiological F2 3′ end cleavage signal is inefficient and that F2 20210 G→A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3′ end processing and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3′ end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210 G→A mutation in the pathogenesis of thrombophilia. This work also illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism.

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Figure 1: The F2 20210 G→A mutation causes an increased abundance of prothrombin protein and mRNA.
Figure 2: The F2 20210 G→A mutation enhances mRNA expression at a post-transcriptional level.
Figure 3: F2*G and F2*A mRNAs have identical 3′ UTRs and poly(A) tail lengths.
Figure 4: The F2 20210 G→A mutation causes an upregulation of 3′ end formation efficiency.

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Acknowledgements

The work of these authors was financially supported by the Deutsche Forschungsgemeinschaft (DFG) and the Fritz-Thyssen-Stiftung.

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Authors and Affiliations

  1. Department of Pediatrics, Charité, Humboldt University, Berlin, Germany

    Niels H. Gehring, Ute Frede, Gabriele Neu-Yilik, Patrick Hundsdoerfer, Barbara Vetter & Andreas E. Kulozik

  2. Gene Expression Programme, EMBL, Heidelberg, Germany

    Matthias W. Hentze

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  1. Niels H. Gehring
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Correspondence to Andreas E. Kulozik.

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Gehring, N., Frede, U., Neu-Yilik, G. et al. Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 28, 389–392 (2001). https://doi.org/10.1038/ng578

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