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.

肥厚型心肌病（HCM）是年轻人猝死的主要原因 成年人。 大多数病例被认为是常染色体显性遗传的结果 遗传的特质。 心脏病理学的显着特征包括 肌肉质量增加，伴有纤维混乱和肌原纤维紊乱 受影响的心肌始终累及室间 隔膜。 游离心室壁也可能参与高达 30% 的 案例。 该项目旨在表征有缺陷的细胞 结构、它们的蛋白质和基因参与混乱和 HCM 家族病例中的心肌紊乱。 活检 来自左隔膜和左心室游离壁的材料将被 从有家族记录的 HCM 患者的导管插入术中获得 发生、非 HCM 心脏病患者以及非 HCM 的移植心脏 患有一系列心肌病的患者。 肌原纤维和 Z 盘将 由甘油心肌纤维制备。 免疫细胞化学 膜细胞骨架蛋白，包括 α-肌动蛋白、结蛋白、血影蛋白 和肌浆网 Ca++-ATPase 将进行，以便 确定缺陷的亚细胞位置。 一维和二维 肌原纤维和非肌原纤维蛋白的电泳和免疫印迹 肌原纤维组分以及 Z 盘和 0.6 M KI 可提取组分 将分析分子量、变化和含量的变化。 特异性抗体将用于筛选 lambda gt11 表达文库 人类心脏 cDNA 的序列，如果改变的蛋白质的基因或密切相关 相关亚型尚未克隆或测序。 克隆的基因或 合成寡核苷酸将用于同时进行的基因组研究 揭示DNA序列的改变。 抗体和 DNA 探针将 最终用于研究心肌紊乱的发病机制 家族性 HCM 功能障碍。