Congenital Myasthenic Syndromes

描述（由申请人提供）：要求支持先天性肌无力综合征（CMS）的多方面调查。CMS是异质性和致残性疾病，其中神经肌肉传递的安全范围受到一种或多种特定机制的损害。我们将使用候选基因的方法来寻找不同CMS的原因，确定突变基因导致CMS的机制，然后使用这些信息来产生结构-功能相关性并设计治疗策略。候选基因方法依赖于确定（1）临床表型，（2）基于终板（EP）的细胞化学和超微结构特征的形态学表型，（3）每个EP的乙酰胆碱（ACh）受体（AChRs）的数量，（4）由体外神经肌肉传递参数反映的电生理表型。通过将突变体和相应的野生型基因工程化到合适的表达系统中，然后通过适当的电生理学和生物化学测试来询问，研究突变基因引起CMS的机制。结构-功能相关性依赖于进一步的诱变研究和对突变蛋白质结构变化改变该蛋白质功能的机制的分析，以及这种改变如何影响神经肌肉传递的安全裕度。治疗策略的基础是确定突变引起的分子缺陷，以及确定的缺陷是否增加或减少对ACh的突触反应。与公共卫生的相关性：先天性肌无力综合征（CMS）是由神经肌肉连接处的蛋白质缺陷引起的。他们经常未被诊断或误诊，但其后果往往是高度致残。CMS将通过多方面的方法进行研究，以改善其诊断，治疗和预防。

DESCRIPTION (provided by applicant): Support is requested for a multifaceted investigation of congenital myasthenic syndromes (CMS). The CMS are heterogeneous and disabling diseases in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). We will use the candidate gene approach to find the cause of different CMS, determine the mechanism by which the mutant gene causes the CMS, and then use this information to generate structure-function correlations and devise strategies for therapy. The candidate gene approach rests on determining (1) the clinical phenotype, (2) the morphologic phenotype based on cytochemical and ultrastructural features of the endplate (EP), (3) the number of acetylcholine (ACh) receptors (AChRs) per EP, (4) the electrophysiologic phenotype reflected by parameters of neuromuscular transmission in vitro. The mechanism by which the mutant gene causes a CMS is investigated by engineering the mutant and corresponding wild-type gene into a suitable expression system which is then interrogated by appropriate electrophysiologic and biochemical tests. Structure-function correlations rest on further mutagenesis studies and on analysis of the mechanism by which a change in the structure of the mutated protein alters the function of that protein, and how this alteration affects the safety margin of neuromuscular transmission. Strategies for therapy are based on determining the molecular defect caused by the mutation and whether the identified defect increases or decreases the synaptic response to ACh. Relevance to Public Health: Congenital myasthenic syndromes (CMS) arise from defects in proteins at the nerve-muscle junction. They frequently go undiagnosed or misdiagnosed yet their consequences are often highly disabling. The CMS will be studied by a multifaceted approach that will improve their diagnosis, treatment, and prevention.