Understanding the impact of disease causing mutations in FIX

了解引起 FIX 突变的疾病的影响

基本信息

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
项目类别：
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

项目摘要

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是由F9基因突变引起的血液凝血障碍，编码血液凝血因子IX（修复）。 F9（改变编码的氨基酸）中的130多种不同的非同义突变至少10个同义突变（不会改变编码的氨基酸）引起该疾病。但是，仅分析了少数的效果，以确定这些效果的确切机制突变有助于解决缺陷。这些知识非常重要，因为这些研究尤其是可能有助于改善重组蛋白质疗法的设计。该提议的重点是了解3个非同义词（Val30ile，Leu383ile和Ala436val）和3 同义突变（Val107Val，Arg162arg和Gln237Gln），固定的结构/活动。我们将使用体外（无细胞）和Ex Vivo（细胞培养）对这些突变进行全面分析评估其对修复功能的确切影响的系统。该项目将增加我们对基因型和表型之间的关系。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design.

DOI：
10.1101/2020.03.30.016832
发表时间：
2020-03-31
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Kames, Jacob;Holcomb, David D;Kimchi-Sarfaty, Chava
通讯作者：
Kimchi-Sarfaty, Chava

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.)
影响因子：
0
作者：
Komar AA
通讯作者：
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.