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

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。 遗传特征。心脏病理的显著特征包括 肌纤维紊乱和肌原纤维紊乱的肌肉质量增加 持续累及室间的受累心肌 隔膜。游离室壁也可能参与高达30%的 案子。这个项目试图描述有缺陷的细胞的特征 结构，它们的蛋白质和基因参与了无序和 家族性肥厚型心肌炎患者的心肌组织紊乱。活组织检查 来自左间隔和左心室游离壁的材料将被 有家族史的肥厚型心肌炎患者导尿术中获得的信息 非肥厚性心肌病心脏病患者和非肥厚性心肌病心脏移植的发生 患有一系列心肌病的患者。肌原纤维和Z-Disk将 从甘油化的心肌纤维中制备。免疫细胞化学 膜-细胞骨架蛋白，包括α-肌动蛋白、结蛋白、血影蛋白 肌浆网Ca++-ATPase将被执行，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法和免疫印迹法 肌原纤维组分和Z-Disc和0.6M KI可提取组分 将分析分子量、变化和含量的变化。 将使用特定抗体来筛选lambda gt11表达文库 人类心脏的cDNA，如果该基因的蛋白改变或接近 相关的异构体尚未克隆或测序。克隆的基因或 合成的寡核苷酸将用于同步的基因组研究，以 发现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和 家族性肥厚性肌病的功能障碍。

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.