SIGNIFICANCE OF TROPONIN C MUTATIONS IN HEART DISEASE

肌钙蛋白 C 突变在心脏病中的意义

• 批准号: 7601964
• 负责人: CHEE CHEW LIM
• 金额: $ 0.11万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-03 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601964
• 关键词: Acids; Amino Acids; Biological Models; Calcium; Calcium Binding; Calcium-Binding Domain; Cardiac; Cardiomyopathies; Computer Retrieval of Information on Scientific Projects Database; Development; Digestion; Funding; Gel; Genetic; Grant; Heart; Heart Diseases; Human; Institution; Link; Manuscripts; Microfilaments; Missense Mutation; Mutation; Myocardial; Myocardial Contraction; Myocardial dysfunction; Numbers; Patients; Peptides; Proteins; Publications; Relative (related person); Research; Research Personnel; Resources; Signal Transduction; Source; Structure-Activity Relationship; Troponin; Troponin C; United States National Institutes of Health; base; design; human disease; mutant; novel; tandem mass spectrometry; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Emerging evidence has linked mutations in myofiliment proteins to the development of genetic cardiomyopathies and myocardial dysfunction. Troponin C is the protein responsible for the transmission of the calcium-binding signal and triggering the contractile cycle. Dr. Liao and her associates have recently identified two novel missense mutations in human cardiac troponin C at amino acid residues 59 (E59D) and 75 (D75Y) from a patient with idiopathic dialated cardiomyopathy, the first identified mutation of troponin C from any human disease. These missense mutations are located within the calcium-binding domain that regulates myocardial contraction, and result in decreased myofilament calcium responsiveness. These preliminary results show mutations in troponin C contribute to the decreased contractile function in the diseased human heart. To determine the structure-function relationship, they have designed a number of troponin C mutants based on replacing specific ami no acid residues located within regulatory calcium-binding domains. We have used in-gel proteolytic digestion, followed by MALDI-TOF and tandem mass spectrometry to structurally verify specific mutations. Additionally, semiquantitation of synthetic mutant peptides has enabled estimation of relative expression levels. Using this mutational model system, it should be possible to define how mutations in cardiac troponin C alter calcium responsiveness in cardiac myofilaments and, consequently, determine myocardial contractility. A manuscript describing the recent results has been submitted for publication.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 新出现的证据已经将肌丝蛋白的突变与遗传性心肌病和心肌功能障碍的发展联系起来。肌钙蛋白C是负责传递钙结合信号并触发收缩周期的蛋白质。Liao博士及其同事最近在一名特发性扩张性心肌病患者的人心肌肌钙蛋白C中发现了两个新的氨基酸残基59（E59 D）和75（D 75 Y）的错义突变，这是第一个从任何人类疾病中发现的肌钙蛋白C突变。这些错义突变位于调节心肌收缩的钙结合结构域内，并导致肌丝钙反应性降低。这些初步结果表明，肌钙蛋白C的突变有助于降低患病人类心脏的收缩功能。为了确定结构-功能关系，他们设计了许多肌钙蛋白C突变体，这些突变体基于替换位于调节性钙结合结构域内的特定氨基酸残基。我们已经使用了凝胶内蛋白水解消化，然后通过MALDI-TOF和串联质谱来验证特定突变的结构。此外，半定量的合成突变体肽已经能够估计相对表达水平。使用这个突变模型系统，它应该是可能的，以确定如何在心肌肌钙蛋白C的突变改变心肌肌丝钙反应性，从而确定心肌收缩力。描述最近结果的手稿已提交出版。