Sarcoglycan in myopathy and muscle membrane stability

描述（由申请人提供）：在肌肉中，肌聚糖复合物由四个主要亚基组成，1-肌聚糖、2-肌聚糖、3-肌聚糖和4-肌聚糖。肌聚糖复合物与肌营养不良蛋白（杜氏肌营养不良基因的蛋白质产物）相互作用，将细胞骨架连接到细胞膜和细胞外基质。编码肌聚糖蛋白的基因突变导致常与心肌病相关的肢带型肌营养不良症的遗传形式。肌聚糖基因突变的表型与杜氏肌营养不良症的表型重叠。与肌营养不良蛋白基因突变一样，疾病的发作和进展存在相当大的变异性，无法用特定的等位基因来解释。这在Sgcg等位基因521-T中清楚地看到，其中该单一突变与肌无力的发病年龄和进展范围相关。在第一个资助期，我们产生了缺乏3-肌聚糖的小鼠，Sgcg无效。我们发现，与人类一样，Sgcg敲除小鼠也显示出一系列表型。在第二个资助期内，我们确定了遗传背景影响疾病的严重程度，现在在7号染色体上绘制了一个主要的修饰基因座。我们还通过删除果蝇中的3/4肌聚糖直系同源物建立了肌营养不良症和心肌病的果蝇模型。使用这些模型，我们已经概述了一个病理序列，开始与膜脆性和异常的渗透性，其次是尝试修复，然后肌纤维和心肌细胞损失伴随着纤维脂肪沉积。我们将利用肌聚糖基因的保守性来了解3-肌聚糖和4-肌聚糖之间的功能差异。我们计划确定负责dMOD 1的基因，7号染色体上的修饰基因座，并测试这种修饰是否也改变了遗传上不同形式的肌营养不良症的结果。最后，我们将利用MRL背景的增强愈合背景来确定改善肌营养不良症心脏和肌肉功能的遗传区域。公共卫生相关性：肌肉萎缩症和相关心脏病的严重程度通常不能用产生疾病的基因突变来解释。我们知道，其他基因区域可以改善或恶化肌肉萎缩症的结果。我们正在进行遗传学研究，以确定改善肌营养不良症的基因，因为了解这些区域将有助于我们更好地预测患者的病情，也因为这些区域可能指向新的治疗途径。

DESCRIPTION (provided by applicant): In muscle, the sarcoglycan complex is composed of four major subunits, 1, 2 3 and 4-sarcoglycan. The sarcoglycan complex interacts with dystrophin, the protein product of the Duchenne Muscular Dystrophy gene, to connect the cytoskeleton to the membrane and the extracellular matrix. Mutations in the genes encoding the sarcoglycan proteins lead to inherited forms of limb girdle muscular dystrophy frequently associated with cardiomyopathy. The phenotype from sarcoglycan gene mutations overlaps with what is seen in Duchenne muscular dystrophy. As with dystrophin gene mutations, there is considerable variability in disease onset and progression that cannot be explained by the specific allele. This is clearly seen with the Sgcg allele, 521-T, where this single mutation has been associated with a range of age of onset and progression of muscle weakness. In the first funding period, we generated mice lacking 3-sarcoglycan, Sgcg null. We found that, as with humans, Sgcg null mice also display a range of phenotype. During this second funding period, we identified that genetic background influences the severity of disease and now mapped a major modifier locus on chromosome 7. We also established a Drosophila model of muscular dystrophy and cardiomyopathy by deleting the 3/4 sarcoglycan ortholog in Drosophila. Using these models, we have outlined a pathologic sequence that initiates with membrane fragility and abnormal permeability that is secondarily following by attempted repair, and then myofiber and cardiomyocyte loss accompanied by fibrofatty deposition. We will use the conservation of sarcoglycan genes to understand functional differences between 3-sarcoglycan and 4-sarcoglycan. We plan to identify the genes responsible for dMOD1, the modifier locus on chromosome 7, and to test whether this modifier also alters the outcome in genetically distinct forms of muscular dystrophy. Finally, we will exploit the enhanced healing background of the MRL background to identify genetic regions that improve heart and muscle function in muscular dystrophy. PUBLIC HEALTH RELEVANCE: Often the severity of muscular dystrophy and associated heart disease is not explained by the genetic mutation that produces the disease. We know that other genetic regions can improve or worsen the outcome in muscular dystrophy. We are conducting genetic studies to identify genes that improve muscular dystrophy because knowing these regions will help us predict better how patients will fare and also because these regions may point to new pathways for therapy.