Patho-Genetic Explorations of Myotilin, the LGMD1A Gene

肌动蛋白 LGMD1A 基因的病理遗传学探索

• 批准号: 7025751
• 负责人: Sean M. Garvey
• 金额: $ 2.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-03 至 2008-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025751
• 关键词: actin binding protein; biopsy; clinical research; gene expression; genetically modified animals; human subject; idiopathic dilated cardiomyopathy; immunocytochemistry; immunoelectron microscopy; laboratory mouse; morphometry; muscle function; muscle proteins; muscular dystrophy; myocardium; pathologic process; point mutation; predoctoral investigator; protein isoforms; protein localization; protein protein interaction; protein structure function; serial analysis of gene expression; single nucleotide polymorphism; striated muscles

DESCRIPTION (provided by applicant): Myotilin protein is expressed specifically in muscle and localizes to the myofiber Z-disc. Two independent missense mutations in the myotilin gene cause Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A), and two separate myotitin missense single nucleotide polymorphisms (SNPs) show a positive association with dilated cardiomyopathy (DCM). The amino acid substitutions resulting from these mutations occur at the N-terminus of myotilin, a domain with no known function. To explore the effects of the LGMD1A mutations on myotilin and muscle function, I propose to perform immunohistochemistry on LGMD1A muscle, targeting myotilin, myotilin-interacting proteins, and additional proteins that localize to the myofiber Z-disc. I propose to construct three mutant myotilin transgenes and thoroughly characterize their effects on muscle function in transgenic mice. Such mice will also provide a wealth of tissue for downstream immunohistochemical and biochemical experiments. I will also characterize a novel myotilin isoform that is expressed predominantly in cardiac muscle, and continue to genotype myotilin SNPs in an expanding set of DCM patients.

描述（由申请人提供）：肌动素蛋白在肌肉中特异性表达，定位于肌纤维z盘。肌凝素基因的两个独立错义突变导致1A型肢体肌萎缩症（LGMD1A），两个独立的肌凝素错义单核苷酸多态性（snp）显示与扩张性心肌病（DCM）呈正相关。由这些突变引起的氨基酸替换发生在肌动素的n端，一个未知功能的结构域。