Molecular mechanisms of hereditary thrombophilia: physiological function of prothrombin mRNA 3` end maturation

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The G A mutation at position 20210 of the prothrombin or coagulation factor II gene (F2) affects about 1-2% of the north-west European population and results in a 3-5-fold increase of the risk of thromboembolic events and is therefore considered to be of public health concern. In clinical studies, this increased risk has been associated with an elevated prothrombin plasma concentration in affected individuals. However, the molecular mechanism of this mutation has been unknown. In the first phase of our work, we established that this mutation results in a gain of function of 3` end RNA processing, which represents a novel principle for the molecular pathogenesis of a genetic disorder. We now plan to functionally charaterise this novel molecular mechanism that results in a medically highly relevant gain of function of RNA maturation and aim to obtain insight into the physiological implications of different levels of 3` end processing efficiency.