Understanding the impact of disease causing mutations in FIX

血友病B是一种凝血障碍，由编码凝血功能的F9基因突变引起。 因子IX（FIX）。F9中超过130种不同的非同义突变（改变编码的氨基酸）， 至少10个同义突变（其不改变编码的氨基酸）引起该疾病。 然而，只有少数的影响进行了分析，以确定确切的机制（S），这些 突变导致FIX缺陷。这些知识是非常重要的，特别是这些研究 可能有助于改进重组蛋白治疗剂的设计。该提案的重点是 了解3个非同义词（Val 30 Ile、Leu 383 Ile和Ala 436 Val）和3个非同义词（Val 30 Ile、Leu 383 Ile和Ala 436 Val） 同义突变（Val 107 Val、Arg 162 Arg和Gln 237 Gln）对FIX的表达、结构/活性的影响。 我们将使用体外（无细胞）和离体（细胞培养）方法对这些突变进行全面分析。 系统，以评估其对FIX功能的确切影响。这个项目将增加我们对 基因型与表型的关系。

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.