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: 6242365
• 负责人: CHRISTINE E SEIDMAN
• 金额: $ 26.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242365
• 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， 导致心脏增大，收缩功能受损， 经常导致心力衰竭。 最近的研究表明， 20%的扩张型心肌病是家族性的，并作为X连锁遗传。 或显性特征。 一些零星的扩张型心肌病病例 发生继发于毒素，感染或全身性疾病，在许多 在某些情况下，病因不明。 该项目建议使用分子 遗传学方法，以确定编码基因的染色体， 会发生变异，导致扩张型心肌病， 常染色体显性遗传方式（FDC）。 使用位置克隆，我们将 找出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 扩张型心肌病遗传病因的探讨 将使临床前诊断在家庭中的风险，并最终将 允许开发这种情况的动物模型， 治疗方式 这个项目的目标是高度融合的 与本心力衰竭SCOR中的其他项目进行比较。 鉴定 负责FDC的基因缺陷将使临床前识别 有心力衰竭风险的个体， 预防性干预。 此外，遗传缺陷的鉴定 这将促进基础研究，以阐明如何肌细胞 结构和功能会因突变蛋白而改变， 来定义补偿反应。 我们认为，了解 由基因突变引发的复杂信号最终会提供 收缩的分子机制的重要见解 导致心力衰竭的功能障碍