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.

Public Health Relevance

Hemophilia B is a blood clotting disorder caused by numerous mutations in the F9 gene, which encodes a serine protease in the blood coagulation system known as factor IX. However, the effects on the molecular level of only a few non-synonymous mutations and none of the synonymous ones in F9 open reading frame have been analyzed to determine the exact mechanism(s) by which these mutations contribute to FIX deficiency. This proposal is aimed at understanding of the exact effects produced by 3 non-synonymous and 3 synonymous mutations in F9 which cause severe and mild hemophilia B, respectively.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-VH-C (80))
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Link, Rebecca P
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Cleveland State University
Schools of Arts and Sciences
United States
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