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: 6272987
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 27.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-26 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272987
• 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.

扩张型心肌病是一种原发性心肌疾病， 导致心脏扩大并伴有收缩功能受损 经常导致心力衰竭。 最近的研究表明，大约 20% 的扩张型心肌病是家族性的，并且是 X 连锁遗传的 或显性特征。 虽然也有一些散发性扩张型心肌病病例 在许多情况下，继发于毒素、感染或全身性疾病 病因不明的情况。 该项目建议使用分子 遗传方法来识别编码基因的染色体 可能发生突变，导致扩张型心肌病，并通过以下途径传播： 常染色体显性时尚（FDC）。 使用定位克隆，我们将 确定导致这种情况的致病基因和突变。 我们还将评估 FDC 基因在引起非家族性心脏病中的作用 失败。 扩张型心肌病遗传原因的鉴定 将为有风险的家庭提供临床前诊断，并最终 允许开发针对这种情况的动物模型，可能会改善 治疗方式。 该项目的目标是高度集成的 以及心力衰竭 SCOR 中其他项目的项目。 鉴定 导致 FDC 的基因缺陷将使临床前识别 有心力衰竭风险的个体并促进纵向研究 和预防性干预措施。 此外，遗传缺陷的鉴定 FDC 将促进基础研究，以阐明肌细胞如何 结构和功能会因突变蛋白质而改变，并有助于 定义补偿反应。 我们相信，了解 基因突变触发的复杂信号最终应提供 对收缩分子机制的重要见解 功能障碍导致心力衰竭。