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

The G-->A mutation at position 20210 of the prothrombin or coagulation fact or II gene (F2) represents a common genetic risk factor for the occurrence of thromboembolic events(1-3). This mutation affects the T-terminal nucleot ide of the 3' untranslated region (UTR) of the mRNA and causes elevated pro thrombin plasma concentrations(1-4) by an unknown mechanism. Here, we show that the mutation does not affect the amount of pre-mRNA, the site of 3' en d 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 inefficien t and that F2 20210 G-->A represents a gain-of-function mutation, causing i ncreased cleavage site recognition, increased Tend processing and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3' end formation ef ficiency emerges as a novel principle causing a genetic disorder and explai ns the role of the F2 20210 G-->A mutation in the pathogenesis of thromboph ilia. This work also illustrates the pathophysiologic importance of quantit atively minor aberrations of RNA metabolism.