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.

血友病B是一种由编码凝血的F9基因突变引起的凝血障碍 因数IX(修正)。F9中130多个不同的非同义突变(改变编码的氨基酸)和 至少有10个同义突变(不会改变编码的氨基酸)会导致这种疾病。 然而，只有少数几个人的影响被分析以确定这些影响的确切机制(S) 突变有助于修复缺陷。这些知识是极其重要的，因为这些研究尤其如此 可能有助于改进重组蛋白疗法的设计。这项提案的重点是 了解3个非同义词(Val30Ile、Leu383Ile和Ala436Val)和3产生的确切效果 FIX在表达、结构/活性上的同义突变(Val107Val、Arg162Arg和Gln237Gln)。 我们将使用体外(无细胞)和体外(细胞培养)对这些突变进行全面分析。 评估其对FIX功能的确切影响的系统。这个项目将增加我们对 基因型与表型的关系。

项目成果

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

• DOI: 10.1038/srep31393
• 发表时间: 2016-08-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Singh J;Sikand K;Conrad H;Will CL;Komar AA;Shukla GC
• 通讯作者: Shukla GC

Unraveling co-translational protein folding: Concepts and methods.

• DOI: 10.1016/j.ymeth.2017.11.007
• 发表时间: 2018-03-15
• 期刊: Methods (San Diego, Calif.)
• 作者: Komar AA

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

• DOI: 10.1136/jmedgenet-2016-104072
• 发表时间: 2017-05
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Simhadri VL;Hamasaki-Katagiri N;Lin BC;Hunt R;Jha S;Tseng SC;Wu A;Bentley AA;Zichel R;Lu Q;Zhu L;Freedberg DI;Monroe DM;Sauna ZE;Peters R;Komar AA;Kimchi-Sarfaty C
• 通讯作者: Kimchi-Sarfaty C

Communication between RACK1/Asc1 and uS3 (Rps3) is essential for RACK1/Asc1 function in yeast Saccharomyces cerevisiae.

• DOI: 10.1016/j.gene.2019.04.087
• 发表时间: 2019-07
• 期刊: Gene
• 影响因子: 3.5
• 作者: Nishant Singh;Supriya Jindal;Arnab Ghosh;A. Komar

Ribosome profiling of HEK293T cells overexpressing codon optimized coagulation factor IX.

• DOI: 10.12688/f1000research.22400.2
• 发表时间: 2020
• 期刊: F1000Research
• 作者: Alexaki A;Kames J;Hettiarachchi GK;Athey JC;Katneni UK;Hunt RC;Hamasaki-Katagiri N;Holcomb DD;DiCuccio M;Bar H;Komar AA;Kimchi-Sarfaty C
• 通讯作者: Kimchi-Sarfaty C