Understanding the impact of disease causing mutations in FIX

了解引起 FIX 突变的疾病的影响

• 批准号: 8752096
• 负责人: Anton A. Komar
• 金额: $ 43.65万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752096
• 关键词: Activated Partial Thromboplastin Time measurement; Affect; Amino Acids; Animal Model; Biological Assay; Blood Coagulation Disorders; Blood coagulation; Brain hemorrhage; Calnexin; Cell Culture System; Cell-Free System; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Coagulants; Codon Nucleotides; Computer Simulation; Data; Databases; Disease; F9 gene; Factor IX; Factor VIIa; Factor XIa; Foundations; Genotype; Hematological Disease; Hemophilia A; Hemophilia B; Hemorrhage; In Vitro; Knowledge; Lead; Location; Measures; Messenger RNA; Modeling; Molecular; Molecular Chaperones; Monitor; Mutation; Mutation Analysis; Nature; Open Reading Frames; Patients; Phenotype; Post-Translational Protein Processing; Process; Property; Protein Biosynthesis; Protein Conformation; RNA; RNA Splicing; Recombinant Proteins; Reporting; Risk; Serine Protease; Site; Structure; System; Testing; Therapeutic; Thromboplastin; Time; Translations; Trauma; Variant; chemical property; design; disease-causing mutation; disorder prevention; gene function; improved; mRNA Expression; mRNA Stability; mutant; protein degradation; protein folding; public health relevance

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.

B 型血友病是一种由 F9 基因突变引起的凝血障碍，该基因编码凝血功能 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）和 至少有 10 个同义突变（不改变编码的氨基酸）导致该疾病。 然而，只有少数的影响被分析以确定这些影响的确切机制。 突变会导致 FIX 缺陷。这些知识极其重要，因为这些研究尤其 可能有助于改进重组蛋白疗法的设计。该提案的重点是 了解 3 个非同义（Val30Ile、Leu383Ile 和 Ala436Val）和 3 个产生的确切效果 FIX 的表达、结构/活性的同义突变（Val107Val、Arg162Arg 和 Gln237Gln）。 我们将使用体外（无细胞）和离体（细胞培养）对这些突变进行全面分析 系统来评估其对 FIX 功能的确切影响。这个项目将加深我们对 基因型和表型之间的关系。

项目成果

The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia.

mRNA 结构在确定血友病同义和非同义突变致病性中的重要性。

• 发表时间: 2017-01
• 作者: Hamasaki;Lin, B C;Simon, J;Hunt, R C;Schiller, T;Russek;Komar, A A;Bar, H;Kimchi
• 通讯作者: Kimchi

Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies.

密码子优化对凝血因子 IX 翻译和结构的影响：对蛋白质和基因治疗的影响。

• 发表时间: 2019
• 影响因子: 4.6
• 作者: Alexaki, Aikaterini;Hettiarachchi, Gaya K;Athey, John C;Katneni, Upendra K;Simhadri, Vijaya;Hamasaki;Nanavaty, Puja;Lin, Brian;Takeda, Kazuyo;Freedberg, Darón;Monroe, Dougald;McGill, Joseph R;Peters, Robert;Kames, Jacob M;Ho
• 通讯作者: Ho

U6atac snRNA stem-loop interacts with U12 p65 RNA binding protein and is functionally interchangeable with the U12 apical stem-loop III.

U6atac snRNA 茎环与 U12 p65 RNA 结合蛋白相互作用，并且在功能上可与 U12 顶端茎环 III 互换。

• 发表时间: 2016-08-11
• 影响因子: 4.6
• 作者: Singh, Jagjit;Sikand, Kavleen;Conrad, Heike;Will, Cindy L;Komar, Anton A;Shukla, Girish C
• 通讯作者: Shukla, Girish C

Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B.

IX 因子中的单一同义突变会改变蛋白质特性，是 B 型血友病的基础。

• 发表时间: 2017-05
• 影响因子: 4
• 作者: Simhadri, Vijaya L;Hamasaki;Lin, Brian C;Hunt, Ryan;Jha, Sujata;Tseng, Sandra C;Wu, Andrew;Bentley, Amber A;Zichel, Ran;Lu, Qi;Zhu, Lily;Freedberg, Darón I;Monroe, Dougald M;Sauna, Zuben E;Peters, Robert;Komar, Anton A;Kim
• 通讯作者: Kim

Properties of the ternary complex formed by yeast eIF4E, p20 and mRNA.

酵母 eIF4E、p20 和 mRNA 形成的三元复合物的特性。

• 发表时间: 2018-04-30
• 影响因子: 4.6
• 作者: Arndt, Nick;Ross;Kojukhov, Artyom;Komar, Anton A;Altmann, Michael
• 通讯作者: Altmann, Michael