Pathogenesis of Emery-Dreifuss Muscular Dystrophy

描述（由申请人提供）：emry - dreifuss肌营养不良症（EDMD）的特征是局部肌肉收缩，缓慢进行性肌肉萎缩和心肌病伴房室传导阻滞。难以区分的EDMD以常染色体显性和x连锁方式遗传。emerin（核膜内膜的一种完整蛋白）的突变导致x连锁EDMD。常染色体显性EDMD是由编码核膜中间丝蛋白A和c的LMNA基因突变引起的，目前尚不清楚核膜蛋白突变是如何引起肌肉萎缩症的。我们假设这些染色质相关蛋白的突变导致负责肌肉细胞分化或存活的基因表达的变化。我们的目标是通过对转染细胞、患者细胞和组织以及动物模型的综合研究来验证这一假设。

DESCRIPTION (provided by applicant): Emery-Dreifuss muscular dystrophy (EDMD) is characterized by region muscle contractures, slow progressive muscle wasting and cardiomyopathy with atrioventricular conduction block. Indistinguishable forms of EDMD are inherited in autosomal dominant and X-linked manners. Mutations in emerin, an integral protein of the nuclear envelope inner membrane, cause X-linked EDMD. Autosomal dominant EDMD is caused by mutations in the LMNA gene, which encodes the nuclear envelope intermediate filament proteins lamins A and C. It is not known how mutations in nuclear envelope proteins cause muscular dystrophy. We hypothesize that mutations in these chromatin-associated proteins cause changes in the expression of genes responsible for muscle cell differentiation or survival. Our goal is to test this hypothesis using a combination of studies in transfected cells, patients' cells and tissues and animals models. In the first specific aim, we will use fluorescence microscopy and photobleaching methods to investigate how lamin A and C mutants from patients with autosomal dominant EDMD influence the mobility of emerin in the inner nuclear membrane. We will determine if mutant lamins A and C cause emerin to "escape" from the inner nuclear membrane into the continuous endoplasmic reticulum. As patients with X-linked EDMD do not have emerin in the inner nuclear membrane, this finding would demonstrate a connection between the X-linked and autosomal dominant forms of the disease. In the second aim, we will use microarrays to compare gene expression in cells from patients with autosomal dominant EDMD to X-linked EDMD and Dunnigan-type partial lipodystrophy, a disease caused by mutations in different regions of lamins A and C. This will establish if emerin and lamin mutations responsible for EDMD alter expression of the same genes. We will also use microarrays to determine gene expression profiles in muscles from lamin A/C "knockout" mice that develop muscular dystrophy and compare the results to what is known about pathologic alterations in gene expression in Duchenne muscular dystrophy. The results will be confirmed in tissues from human subjects with EDMD. In Aim 3, we will generate transgenic mice expressing human lamin A mutants and determine if they develop pathological abnormalities of EDMD and similar gene expression changes. This work will help establish how abnormalities in the nuclear envelope cause muscular dystrophy.