Novel pathogenic mechanisms implicated in defects of neuromuscular transmission

先天性肌无力综合征（CMS）是一组导致儿童和成人肌无力的遗传性疾病。CMS影响神经肌肉接头（NMJ），这是一种负责将信号从神经传递到肌肉的连接结构，导致肌肉收缩。当这一环节中断或功能效率降低时，患者很快就会感到疲劳，并可能严重残疾。当呼吸肌肉受到影响时，这种情况可能危及生命。我们最近发现了一种名为GFAT 1的新基因的突变，这种突变导致了一种以前未被认识到的CMS形式。目前，尚不清楚GFAT 1突变如何干扰NMJ功能和结构导致CMS。我们已经发现，与健康对照肌肉相比，患者肌肉组织中存在的GFAT 1蛋白的量大大减少。因此，我们的目的是研究GFAT 1丧失对肌肉功能以及神经和肌肉之间的通讯的影响。许多蛋白质在其表面上携带糖残基，这对其功能很重要。GFAT 1酶产生一种代谢物，对于将糖残基添加到蛋白质上的所有反应都是必不可少的。我们计划研究蛋白质是否在GFAT 1患者中失去糖修饰，哪些蛋白质受此影响最大，以及对肌肉细胞正确功能的影响。由于蛋白质的糖修饰是所有细胞类型中非常普遍的机制，我们的结果不仅可以提高我们对CMS的认识，而且有助于理解阿尔茨海默病等疾病中神经细胞蛋白质的糖修饰。2型糖尿病的发病机制是什么？

Congenital myasthenic syndromes (CMS) are a group of inherited diseases that cause muscle weakness in children and adults. CMS affect the neuromuscular junction (NMJ), a link structure that is responsible for transmitting signals from nerves to muscles, causing muscles to contract. When this link breaks down, or functions less efficiently, the patient gets tired very quickly and can be severely disabled. The condition may be life-threatening, when breathing muscles are affected. We have recently discovered mutations in a new gene called GFAT1 which cause a previously unrecognised form of CMS. At the moment it is not yet understood how mutations in GFAT1 interfere with NMJ function and structure to cause CMS. We have found out that the amount of GFAT1 protein present in the muscle tissue of patients is considerably diminished compared to healthy control muscle. Our aim is therefore to study the consequences of the loss of GFAT1 for muscle function and for communication between nerve and muscle. Many proteins carry sugar residues on their surface which are important for their function. The GFAT1 enzyme produces a metabolite that is essential for all reactions that add sugar residues onto proteins. We plan to investigate whether proteins lose their sugar modification in GFAT1 patients, which proteins are affected most by this and what the implications are for the correct function of a muscle cell.As sugar modification of proteins is a very general mechanism in all cell types, our results may not only improve our knowledge of CMS, but also contribute to the understanding of sugar modifications on proteins of the nerve cells in diseases such as Alzheimer?s disease and in muscle for the development of type 2 diabetes.