The roles of laminin and its membrane receptors on muscular dystrophies

原发性缺裂蛋白型先天性肌营养不良症（CMD）是由α2链基因突变引起的，其特征是婴儿早期骨骼肌发生明显的营养不良性改变。然而，对肌纤维变性的病理过程知之甚少。我们对10例原发性缺裂球蛋白CMD患者的骨骼肌进行了免疫组化分析，使用了一组膜蛋白、细胞坏死和凋亡的分子标记。在最年轻的患者（52天大的婴儿）中，发生了显著的大量肌细胞变性，与MAC的沉积相关，MAC是坏死的标志物。此外，我们发现了散在的凋亡阳性信号。在其他6名1岁以下的患者中观察到类似但较轻的变化，但在3岁以上的患者中几乎检测不到变化。这些结果表明，大量的肌纤维变性发生在非常早期的merosin缺陷的CMD，并可能有助于从婴儿早期肌肉的严重营养不良性变化。福山型先天性肌营养不良症（FCMD）的特点是严重的营养不良性肌肉萎缩从婴儿早期与结构性脑异常。FCMD基因编码一种新的蛋白质，命名为fuklavin，但其功能尚不清楚。为了阐明fuklavin的作用，在FCMD患者和对照组的骨骼肌和心肌中进行免疫组织化学和免疫印迹分析。我们发现FCMD患者肌纤维表面膜上高度糖基化的α-肌营养不良蛋白聚糖（α-DG）选择性缺乏，而β-DG无此现象。免疫印迹分析显示FCMD中α-DG无免疫反应带，β-DG阳性。目前的研究结果表明，在FCMD患者的α-DG的糖基化的损失或修改，这可能会导致肌纤维的跨膜分子连接的关键中断的fuklatin基因突变的关键作用。

Primary merosin-deficient congenital muscular dystrophy (CMD), which is caused by mutations in the 1aminin α2 chain gene, is characterized by marked dystrophic changes in skeletal muscles during early infancy. However little is known about the pathological process of the muscle fiber degeneration. We performed the immunohistochemical analysis of skeletal muscle in ten patients with primary merosin-deficient CMD using a panel of molecular markers for membrane proteins, cellular necrosis, and apoptosis. In the youngest patient (a 52 days old baby), prominent massive muscle cell degeneration occurred in association with the deposition of MAC, a marker of necrosis.In addition, we found scattered positive signals for apoptosis. Similar but milder changes were observed in six other patients younger than 1 year, but barely detectable in the patients older than 3 years. These findings imply that massive muscle fiber degeneration occurs in the very early stage of merosin-deficient CMD and may contribute to the severe dystrophic changes in muscle from early infancy.Fukuyama type congenital muscular dystrophy (FCMD) is characterized by severe dystrophic muscle wasting from early infancy with structural brain abnormalities. The FCMD gene encodes a novel protein named fukutin, but its function is not known yet. To elucidate the roles of fukutin, immunohistochemical and immunoblot analyses were performed in skeletal and cardiac muscles from patients with FCMD and controls. We found a selective deficiency of highly glycosylated α-dystroglycan (α-DG), but not β-DG, on the surface membrane of muscle fibers in patients with FCMD. Immunoblot analyses showed no immunoreactive band for α-DG, but positive for β-DG in FCMD. The present findings suggest a critical role for fukutin gene mutation in the loss or modification of glycosylation of α-DG, which may cause a crucial disruption of the transmembranous molecular linkage of muscle fibers in patients with FCMD.