Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice
Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice
复制标题
DOI：
10.1093/hmg/ddn386
复制
发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Puckelwartz, Megan J.;Kessler, Eric;McNally, Elizabeth M.
编码内核膜蛋白核纤层蛋白A和C的基因突变产生心脏和骨骼肌功能障碍，称为Emery Dreifuss肌营养不良症。核纤层蛋白A和C参与LINC复合物，该复合物沿着nesprin和SUN蛋白，将核骨架与细胞骨架连接。Nesprins 1和2是含有巨大血影蛋白重复序列的蛋白质，具有大小形式。巢蛋白含有一个跨膜锚，其系在核膜上，随后是一个短结构域，其位于核膜内外之间的管腔内。Nesprin的管腔结构域直接与SUN蛋白结合。我们产生了nesprin-1的C-末端缺失的小鼠。这种策略产生了一种缺乏跨膜和腔结构域的蛋白质，这些结构域一起被称为KASH结构域。这种突变的纯合子小鼠表现出致死性，大约一半在出生时或出生时死于呼吸衰竭。存活的小鼠表现出后肢无力和步态异常。随着年龄的增长，脊柱后凸，肌肉病理和心脏传导缺陷的发展。LINC复合物的蛋白组分，包括突变体nesprin-1 α、核纤层蛋白A/C和SUN 2，在该模型中定位于核膜。然而，LINC组件通常不关联，因为SUN 2和nesprin的共免疫沉淀实验表明，突变nesprin-1蛋白不再与SUN 2相互作用。这些发现证明了LINC复合物和nesprin-1在神经肌肉和心脏疾病中的作用。
Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton. Nesprins 1 and 2 are giant spectrin-repeat containing proteins that have large and small forms. The nesprins contain a transmembrane anchor that tethers to the nuclear membrane followed by a short domain that resides within the lumen between the inner and outer nuclear membrane. Nesprin's luminal domain binds directly to SUN proteins. We generated mice where the C-terminus of nesprin-1 was deleted. This strategy produced a protein lacking the transmembrane and luminal domains that together are referred to as the KASH domain. Mice homozygous for this mutation exhibit lethality with approximately half dying at or near birth from respiratory failure. Surviving mice display hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology and cardiac conduction defects develop. The protein components of the LINC complex, including mutant nesprin-1 alpha, lamin A/C and SUN2, are localized at the nuclear membrane in this model. However, the LINC components do not normally associate since coimmunoprecipitation experiments with SUN2 and nesprin reveal that mutant nesprin-1 protein no longer interacts with SUN2. These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease.