Nuclear membrane protein interaction in heart and muscle disease

描述（由申请人提供）：核膜缺陷已成为心脏和神经肌肉疾病的重要介质。编码中间纤维蛋白层蛋白A和C的基因突变是显性遗传性肌肉疾病的常见形式之一，可导致心肌病和肌肉萎缩症。层粘连蛋白A和C在终末分化的细胞类型中表达更高，包括心肌细胞、骨骼肌纤维和神经元。与横纹肌疾病相关的大多数基因突变以常染色体显性遗传方式遗传，其中显性阴性或单倍体不足的遗传机制可能发生并导致疾病。层粘连蛋白A和C的缺失导致细胞的机械核功能受损。我们假设核膜的蛋白质组成可能在心肌细胞和骨骼肌中是特化的，并且横纹肌细胞核膜内的蛋白质相互作用可能在响应层粘连蛋白A和C基因突变时受到干扰。为此，我们对nesprin11进行了表征，这是一种由nesprin1基因座产生的较小的蛋白。Nesprins是核膜相关的含有谱蛋白重复序列的蛋白。在它们的全长形式中，nesprins是一种巨大的蛋白质，可以结合到外核膜上，在那里它们可以参与细胞核在细胞内的定位。nesprin11是一种较小的产物，包含6个谱蛋白重复序列，位于核膜内。nesprin11 mRNA和蛋白在心肌和骨骼肌中均高表达。此外，nesprin11在体外直接与lamin A结合，并且nesprin11需要lamin A或lamin C才能在细胞内正确定位。本文概述了横纹肌核膜中蛋白质相互作用的实验，以及这些相互作用在心脏和骨骼肌疾病中的作用。相关性：编码核膜蛋白的基因突变是影响心脏电系统和肌肉萎缩的心肌病的常见原因。我的实验室对确定核膜的改变是如何导致肌肉疾病很感兴趣。

DESCRIPTION (provided by applicant): Defects of the nuclear membrane have emerged as an important mediator of cardiac and neuromuscular disease. Mutations in the gene encoding the intermediate filament proteins lamins A and C occur as one of the more common forms of dominantly inherited muscle disease leading to cardiomyopathy as well as muscular dystrophy. Lamins A and C are more highly expressed in terminally differentiated cell types including cardiomyocytes, skeletal myofibers and neurons. The majority of genetic mutations associated with striated muscle disease are inherited in an autosomal dominant manner where dominant negative or haploinsufficient genetic mechanisms may occur and lead to disease. Loss of lamins A and C produces cells that have impaired mechanical nuclear function. We hypothesize that the protein composition of the nuclear membrane may be specialized in cardiomyocytes and skeletal muscle, and that protein interactions within the nuclear membrane of striated muscle cells may be perturbed in response to lamin A and C gene mutations. To this end, we have characterized nesprin-11, a smaller protein generated from the nesprin-1 locus. Nesprins are nuclear membrane- associated spectrin repeat-containing proteins. In their full length form, nesprins are giant proteins that can bind to the outer nuclear membrane where they may participate in localizing the nucleus within the cell. Nesprin-11 is a smaller product that contains six spectrin repeats and is localized at the inner nuclear membrane. Nesprin-11 mRNA and protein are both highly expressed in cardiac and skeletal muscle. Moreover, nesprin-11 directly binds to lamin A in vitro, and nesprin-11 requires lamin A or lamin C for proper localization within cells. This proposal outlines experiments to elucidate protein interactions in the striated muscle nuclear membrane and the role of these interactions in cardiac and skeletal muscle disease. RELEVENCE: Mutations in genes that encode proteins of the nuclear membrane are a common cause of cardiomyopathy that affects the electrical system of the heart and muscular dystrophy. My laboratory is interesting in determining how changing the nuclear membrane leads to muscle disease.