Patho-Genetic Explorations of Myotilin, the LGMD1A Gene

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。

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.