Mapping Novel Disease Genes for Dilated Cardiomyopathy

绘制扩张型心肌病的新疾病基因图谱

• 批准号: 7892266
• 负责人: Timothy Mark OLSON
• 金额: $ 28.71万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892266
• 关键词: 10q; 17q; Arrhythmia; Candidate Disease Gene; Cardiac; Cessation of life; Chromosome Mapping; Chromosomes; Cytoskeletal Proteins; DNA Sequence; Databases; Defect; Diagnosis; Diagnostic tests; Dilated Cardiomyopathy; Disease; Early Diagnosis; Exons; Family; Frequencies; Genes; Genetic; Genomics; Genotype; Haplotypes; Heart Transplantation; Heart failure; Human; Human Genetics; Individual; Inherited; Investigation; Ion Channel; Knowledge; Lead; Link; Maps; Mechanics; Metabolic; Molecular; Mutation; Mutation Spectra; Myocardium; Pathway interactions; Patients; Physiological; Prevention; Primary idiopathic dilated cardiomyopathy; Public Health; Research Personnel; Scanning; Statistical Methods; System; Translating; Work; advanced disease; base; cohort; gene discovery; genetic linkage analysis; genome-wide linkage; improved; insight; novel; prevent; programs; sensor

DESCRIPTION (provided by applicant): Idiopathic dilated cardiomyopathy (DCM), a heritable disorder causing human heart failure, has been traditionally attributed to mutations in genes encoding contractile and cytoskeletal proteins. Recent human genetic studies have uncovered defects in distinct molecular pathways, indicating that DCM does not exclusively arise from primary mechanical or structural deficits. Despite these advances, the molecular basis for this disorder is unknown in the vast majority of patients with familial and sporadic disease, emphasizing the necessity for further human genetic investigations. This proposal is based on recruitment and phenotypic characterization of 17 multigenerational families with monogenic DCM, suitable for disease gene mapping, and on a cohort of 449 unrelated individuals with DCM. The first aim is to map chromosomal loci for familial DCM. This will be accomplished by genome-wide linkage analysis. The second aim is to define critical subchromosomal regions for the identification and selection of candidate genes for DCM. The third aim is to identify mutations in positional candidate genes that segregate with DCM. Novel genes, once identified, will be screened for to determine the frequency and spectrum of mutations in patients with familial and sporadic DCM. These aims will be achieved by capitalizing on contemporary genomic databases and by utilization of high throughput systems for genotyping, mutation scanning, and DNA sequencing. The overall objective of this work is to provide new insight into the molecular basis of heart failure and to improve prediction, prevention, and treatment of DCM. Relevance to public health: Dilated cardiomyopathy (DCM) is a major public health problem, resulting in heart failure, arrhythmia, and death. DCM is the most common reason for cardiac transplantation, due to lack of diagnostic tests for early detection and ineffective treatments in advanced disease. Discovering the genetic basis of DCM will lead to better ways to diagnose and prevent the progressive weakening of heart muscle that afflicts patients with this disorder.

描述（由申请人提供）：特发性扩张性心肌病（DCM）是一种遗传性疾病，导致人类心力衰竭，传统上归因于编码收缩性和细胞骨架蛋白质的基因突变。最近的人类遗传研究发现了不同分子途径的缺陷，表明DCM并非仅来自原发性机械或结构缺陷。尽管有这些进展，但在绝大多数家族性和零星疾病的患者中，这种疾病的分子基础尚不清楚，这强调了进行进一步的人类遗传研究的必要性。该建议基于17个具有单基因DCM的多代家族的募集和表型表征，适用于疾病基因映射，以及由449个无关DCM的人组成的。第一个目的是为家族性DCM绘制染色体基因座。这将通过全基因组链接分析来实现。第二个目的是定义关键的亚染色体区域，以鉴定和选择DCM的候选基因。第三个目的是确定与DCM分离的位置候选基因中的突变。一旦鉴定出来的新型基因将被筛选，以确定家族性和零星DCM患者突变的频率和频谱。这些目标将通过利用当代基因组数据库以及利用高吞吐量系统进行基因分型，突变扫描和DNA测序来实现。这项工作的总体目标是提供有关心力衰竭分子基础的新见解，并改善DCM的预测，预防和治疗。 与公共卫生有关：扩张的心肌病（DCM）是一个主要的公共卫生问题，导致心力衰竭，心律不齐和死亡。 DCM是心脏移植的最常见原因，这是由于缺乏早期检测和晚期疾病治疗无效治疗的诊断测试。发现DCM的遗传基础将导致更好的方法来诊断和防止患有这种疾病的患者的心肌逐渐衰弱。