IDENTIFICATION OF GENE DEFECTS THAT CAUSE FAMILIAL DILATED CARDIOMYOPATHIES

鉴定导致家族性扩张型心肌病的基因缺陷

• 批准号: 6110371
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 29.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110371
• 关键词: RNase protection assay; artificial chromosomes; biological polymorphism; cytogenetics; family genetics; genetic disorder; genetic mapping; human subject; molecular genetics; myocardium disorder; nucleic acid sequence

Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function that frequently causes heart failure. Recent studies suggest that approximately 20% of dilated cardiomyopathies are familial and inherited as an X-linked or dominant trait. While some sporadic cases of dilated cardiomyopathy occur secondary to toxins, infection, or systemic illness, in many instances the etiology is unknown. This project proposes to use molecular genetic approaches to identify the chromosome(s) that encode genes which can be mutated to cause dilated cardiomyopathies that are transmitted in an autosomal dominant fashion (FDC). Using positional cloning we will identify both the causal genes and mutations that produce this condition. We will also assess the role of the FDC genes in causing nonfamilial heart failure. Identification of the genetic cause of dilated cardiomyopathy will enable preclinical diagnosis in families at risk and will eventually permit development of animal models for this condition that may improve therapeutic modalities. The goals of this project are highly integrated with those of other projects in this Heart Failure SCOR. Identification of the gene defect responsible for FDC will enable preclinical recognition of individuals at risk for heart failure and foster both longitudinal studies and preventive interventions. Further, identification of a genetic defect that causes FDC will foster basic studies to elucidate how myocyte structure and function are altered in response to mutated proteins and help to define compensatory responses. We believe that understanding the complex signals triggered by gene mutation should ultimately provide important insights into the molecular mechanisms for contractile dysfunction that cause heart failure.

扩张的心肌病是心肌的主要疾病 产生心脏增大，具有收缩功能受损的功能 经常引起心力衰竭。 最近的研究表明 20％的扩张心肌病是家族性的，并作为X连锁 或主导特征。 虽然一些零星的心肌病病例 发生在毒素，感染或全身性疾病的继发性中。 实例病因未知。 该项目建议使用分子 鉴定编码基因的染色体的遗传方法 可以突变以引起扩张的心肌病，并在 常染色体主导时尚（FDC）。 使用位置克隆，我们将 确定产生这种情况的因果基因和突变。 我们还将评估FDC基因在引起非家庭心脏的作用 失败。 鉴定出遗传学的遗传病因 将在有风险的家庭中实现临床前诊断，并最终 允许为这种情况开发动物模型，以改善 治疗方式。 该项目的目标是高度整合的 与此心衰竭得分中的其他项目相关。 识别 负责FDC的基因缺陷将使临床前识别 患有心力衰竭和促进纵向研究的人 和预防干预措施。 此外，识别遗传缺陷 导致FDC会促进基础研究以阐明肌细胞 对突变蛋白的响应改变了结构和功能，并有助于 定义补偿性反应。 我们相信了解 基因突变触发的复杂信号应最终提供 对收缩分子机制的重要见解 引起心力衰竭的功能障碍。