Muntoni Francesco, Brockington Martin, Blake Derek J, Torelli Silvia, Brown Susan C
The Dubowitz Neuromuscular Centre, Department of Paediatrics, Imperial College London, Hammersmith Hospital Campus, W12 0NN, London, UK.
Lancet. 2002 Nov 2;360(9343):1419-21. doi: 10.1016/S0140-6736(02)11397-3.
Over the past 15 years the causative genes of several inherited muscular dystrophies have been identified. These genes encode sarcolemmal, extracellular matrix, sarcomeric, and nuclear envelope proteins. Although the post-translational processing of muscle proteins has a significant role in their correct assembly and function, these processes have not been shown to be primarily involved in the pathogenesis of muscular dystrophies until recently. In the past 18 months, four different forms of inherited muscular dystrophy in human beings have been associated with mutations in genes encoding for putative glycosyltransferases. Aberrant glycosylation of alpha-dystroglycan, an external membrane protein expressed in muscle, brain, and other tissues, is a common feature in these disorders. alpha-dystroglycan is highly glycosylated, its sugar components varying in different tissues and controlling its interaction with extracellular matrix partners. Disrupted glycosylation of alpha-dystroglycan results in a loss of these interactions, giving rise to both progressive muscle degeneration and abnormal neuronal migration in the brain.
Kevin Campbell and colleagues have recently demonstrated that patients with muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD), as well as the myodystrophy (myd) mouse, have an abnormally glycosyated form of alpha-dystroglycan (Nature 2002; 418: 417-22 and 422-25). The abnormally glycosylated protein did not bind to three of its extracellular matrix ligands, laminin alpha2 chain, agrin, and neurexin. The investigators also showed that a neuronal migration disorder occurs in both the myd mouse and in a brain-restricted alpha-dystroglycan knock-out mouse that is similar to that seen in patients with MEB and FCMD. These results identify alpha-dystroglycan as having an essential role in both muscle and brain development and function.
Emphasis is moving away from identifying the protein components of the muscle fibre that are involved in muscular dystrophies towards the post-translational processing of proteins and the enzymes involved in these modifications. This opens up new avenues of research. Abnormal glycosylation of alpha-dystroglycan may underlie other as yet uncharacterised forms of muscular dystrophy and neuronal migration disorders.
在过去15年中，几种遗传性肌营养不良症的致病基因已被确定。这些基因编码肌膜、细胞外基质、肌节和核膜蛋白。尽管肌肉蛋白的翻译后加工在其正确组装和功能中起着重要作用，但直到最近，这些过程尚未被证明主要参与肌营养不良症的发病机制。在过去18个月里，人类四种不同形式的遗传性肌营养不良症与编码假定糖基转移酶的基因突变有关。α- dystroglycan（一种在肌肉、大脑和其他组织中表达的细胞外膜蛋白）的异常糖基化是这些疾病的一个共同特征。α- dystroglycan高度糖基化，其糖成分在不同组织中有所不同，并控制其与细胞外基质伙伴的相互作用。α- dystroglycan糖基化的破坏导致这些相互作用的丧失，从而导致进行性肌肉变性和大脑中异常的神经元迁移。
凯文·坎贝尔及其同事最近证明，患有肌肉-眼-脑疾病（MEB）和福山先天性肌营养不良症（FCMD）的患者，以及肌营养不良（myd）小鼠，都有一种异常糖基化形式的α- dystroglycan（《自然》2002年；418：417 - 22和422 - 25）。这种异常糖基化的蛋白质不与它的三种细胞外基质配体（层粘连蛋白α2链、集聚蛋白和接触蛋白相关蛋白）结合。研究人员还表明，在myd小鼠和一种大脑特异性α- dystroglycan基因敲除小鼠中都出现了神经元迁移障碍，这与在MEB和FCMD患者中看到的情况相似。这些结果表明α- dystroglycan在肌肉和大脑发育及功能中具有重要作用。
研究重点正从确定参与肌营养不良症的肌纤维蛋白成分转向蛋白质的翻译后加工以及参与这些修饰的酶。这开辟了新的研究途径。α- dystroglycan的异常糖基化可能是其他尚未明确的肌营养不良症和神经元迁移障碍形式的基础。
