DNA LINKAGE--A GENE(S) RESPONSIBLE FOR FAMILIAL DILATED CARDIOMYOPATHY

DNA连锁——导致家族性扩张型心肌病的基因

• 批准号: 6110444
• 负责人: Robert E Roberts
• 金额: $ 17.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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/6110444
• 关键词: autosomal dominant trait; echocardiography; family genetics; genetic markers; human genetic material tag; human subject; hypertrophic myocardiopathy; linkage mapping; molecular cloning; nucleic acid repetitive sequence; open reading frames; species difference

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young adults. Most cases are believed to be the result of an autosomal dominant inherited trait. Salient features of the cardiac pathology include increased muscle mass with fiber disorganization and myofibrillar disarray of the affected myocardium which consistently involves the interventricular septum. The free ventricular wall may also be involved in up to 30% of cases. This project seeks to characterize the defective cellular structures, their proteins and genes involved in the disarray and disorganization of the myocardium in familial cases of HCM. Biopsy material from the left septum and left ventricular free wall will be obtained from catheterization of HCM patients with documented familial occurrence, non-HCM cardiac patients, and from explanted hearts of non-HCM patients with a spectrum of cardiomyopathies. Myofibrils and Z-discs will be prepared from glycerinated myocardial fibers. Immunocytochemistry of membrane-cytoskeletal proteins including alpha-actinin, desmin, spectrin and sarcoplasmic reticulum Ca++-ATPase will be performed in order to determine the subcellular location of the defect. One- and two-dimensional electrophoresis and immunoblotting of proteins from myofibrillar and non- myofibrillar fractions and from Z-disc and 0.6 M KI-extractable fractions will be analyzed for alterations in molecular weight, change, and content. Specific antibodies will be used to screen a lambda gt11 expression library of human cardiac cDNAs, if the gene for the altered protein or closely related isoform is not already cloned or sequenced. The cloned gene or synthetic oligonucleotide will be used in concurrent genomic studies to uncover the DNA sequence alteration. The antibody and DNA probes will ultimately be used to study the pathogenesis of myocardial disarray and dysfunction in familial HCM.

肥厚性心肌病（HCM）是年轻人突然死亡的主要原因 成年人。 据信大多数情况是常染色体显性的结果 继承的特质。 心脏病理的显着特征包括 随着纤维混乱和肌原纤维混乱而增加肌肉质量 受影响的心肌，始终涉及介入 隔膜。 自由心室壁也可能涉及多达30％ 案例。 该项目旨在表征有缺陷的蜂窝 结构，蛋白质和基因涉及混乱和 HCM家族病例中心肌的混乱。 活检 左隔和左心室的材料将是 从HCM患者的导管插入术有记录的家族性 发生，非HCM心脏患者，以及非HCM的外植型心脏 患有多种心肌病的患者。 肌原纤维和Z盘将 从甘油中的心肌纤维中制备。 免疫细胞化学 膜细胞骨架蛋白，包括α-肌动蛋白，脱敏蛋白，光谱蛋白 将进行肌浆网++ -ATPase，以便为了 确定缺陷的亚细胞位置。 一维和二维 肌原纤维和非 - 非蛋白质的电泳和免疫印迹 肌原纤维分数和Z-DISC和0.6 M KI可提取的分数 将分析分子量，变化和内容的改变。 特定抗体将用于筛选lambda GT11表达式库 人类心脏cDNA，如果是改变的蛋白质或紧密的基因 相关的同工型尚未克隆或测序。 克隆的基因或 合成寡核苷酸将用于并发基因组研究 发现DNA序列改变。 抗体和DNA探针将 最终用于研究心肌混乱的发病机理和 家族性HCM功能障碍。