Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA.
Dev Cell. 2013 Sep 30;26(6):591-603. doi: 10.1016/j.devcel.2013.08.012. Epub 2013 Sep 19.
X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.
X 连锁先天性肌营养不良是由核膜内层固有蛋白 emerin 的功能丧失引起的。然而，emerin 缺失的小鼠基本正常，这表明存在关键的补偿因素。我们发现核膜层粘连蛋白 1（LAP1）与 emerin 相互作用。横纹肌中 LAP1 的条件性缺失会导致肌肉疾病；在没有 emerin 的情况下，这种病理会加重。LAP1 在小鼠肌肉中的水平显著高于人类，并且将 LAP1 减少约一半也会导致 emerin 缺失的小鼠出现肌肉异常。肝细胞中 LAP1 的条件性缺失可产生肝功能正常的小鼠，与同窝对照小鼠无明显区别。这些结果表明 LAP1 与 emerin 具有物理和功能相互作用，并在维持骨骼肌中发挥重要且选择性的作用。它们还强调了如何剖析小鼠和人类表型之间的差异，可以为疾病机制提供基本的见解。
