Congenital Myasthenic Syndromes

先天性肌无力综合症

• 批准号: 7613413
• 负责人: ANDREW George ENGEL
• 金额: $ 53.82万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613413
• 关键词: Acetylcholine; Affect; Biochemical; Candidate Disease Gene; Cholinergic Receptors; Congenital Myasthenic Syndromes; Defect; Diagnosis; Engineering; Finding by Cause; Genes; In Vitro; Investigation; Molecular; Muscle; Mutagenesis; Mutate; Mutation; Nerve; Phenotype; Prevention; Proteins; Public Health; Research Personnel; Rest; Safety; Structure; Synapses; System; Testing; base; clinical phenotype; disabling disease; improved; mutant; neuromuscular transmission; programs; protein function; response

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.

描述（由申请人提供）：要求对先天性肌关系综合征（CMS）进行多方面调查。 CMS是异质性和致残性疾病，其中神经肌肉传播的安全边缘被一种或多种特定的机制损害。我们将使用候选基因方法来找到不同CM的原因，确定突变基因引起CMS的机制，然后使用此信息来产生结构功能相关性并制定治疗策略。 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.突变基因引起CMS的机制通过工程化突变体并将相应的野生型基因与合适的表达系统进行了研究，然后通过适当的电生理学和生化测试对其进行询问。结构 - 功能相关性基于进一步的诱变研究和分析突变蛋白结构变化的机制，改变了该蛋白质的功能，以及这种改变如何影响神经肌肉传播的安全边缘。治疗的策略是基于确定由突变引起的分子缺损以及确定的缺陷是否增加还是减少对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）是由神经肌肉结的蛋白质缺陷引起的。他们经常没有被诊断或误诊，但其后果通常是高度致残的。 CMS将通过一种多方面的方法来研究，该方法将改善其诊断，治疗和预防。