Understanding the impact of disease causing mutations in FIX

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Hemophilia B is a blood clotting disorder caused by mutations in the F9 gene, encoding the blood coagulation factor IX (FIX). Over 130 different non-synonymous mutations in F9 (which change encoded amino acids) and at least 10 synonymous mutations (which do not change the encoded amino acids) cause the disease. However, the effects of only a few have been analyzed to determine the exact mechanism(s) by which these mutations contribute to FIX deficiency. Such knowledge is extremely important as these studies in particular might help to improve the design of recombinant protein therapeutics. This proposal is focused on understanding the exact effects produced by 3 non-synonymous (Val30Ile, Leu383Ile and Ala436Val) and 3 synonymous mutations (Val107Val, Arg162Arg and Gln237Gln) on the expressions, structure/activity of FIX. We will conduct a comprehensive analysis of these mutations using in vitro (cell-free) and ex vivo (cell culture) systems to assess their exact impact on FIX function. This project will add to our understanding of the relationship between genotype and phenotype.