CONGENITAL MYASTHENIC SYNDROMES

描述：(改编自调查员摘要)的总体目标 这项建议是为了研究先天性心脏病的病理机制。 肌无力综合征(CMS)。CMS是高度致残的障碍，在 神经肌肉传递的安全边际受到 一个或多个具体机制(S)。CMS并不少见，但 很少被正确诊断或治疗。适当的形态和 然而，电生理分析可以识别所涉及的缺陷。 此外，这样的研究可能会牵涉到候选突变蛋白或 基因；例如，运动的电生理学识别 AChR异常是AChR突变的推定证据 亚单位。合作医疗的方法将通过五个步骤进行：(1) 临床评估，包括肌电图和抗AchR试验 抗体；(2)形态评估，包括细胞化学或 乙酰胆碱酯酶、AChR和AChR的免疫细胞化学定位 终板上的亚基(EP)，每个EP的AChR数量的估计， EP的定量超微结构分析及对EP的评价 AChR在交界褶皱上的密度和分布； 电生理学评估，由常规微电极组成 极压电位和电流的研究，参数的估计 量子释放和通过噪声评估AChR通道动力学 分析和单通道膜片钳记录；(4)突变 AChR动力学异常时AChR亚基的分析 可识别的；以及(5)使用遗传技术的协作表达研究 当AChR亚单位突变被鉴定时，工程突变体AChR。这个 建议的研究对诊断、治疗和预防具有重要意义。 以及对突触功能的更多了解 和AChR的结构-功能关系。此外，认识到 EP烟碱型AChR的自发突变应该会刺激对 神经型烟碱型乙酰胆碱受体和其他配体门控通道的突变 各种神经学和精神障碍。

DESCRIPTION: (Adapted from investigator's abstract) The broad aim of this proposal is to examine pathologic mechanisms in congenital myasthenic syndromes (CMS). The CMS are highly disabling disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). The CMS are not uncommon but are seldom diagnosed or treated correctly. Appropriate morphologic and electrophysiologic analysis, however, can identify the defects involved. Furthermore, such studies can implicate a candidate mutant protein or gene; for example, the electrophysiologic identification of a kinetic abnormality of AChR is presumptive evidence for a mutation in an AChR subunit. The approach to the CMS will be through five steps: (1) clinical assessment, including electromyography and tests for anti- AchR antibodies; (2) morphologic assessment, including cytochemical or immunocytochemical localization of acetylcholinesterase, AChR, and AChR subunits at the endplate (EP), estimate of the number of AChR per EP, quantitative ultrastructural analysis of the EP, and evaluation of the density and distribution of AChR on the junctional folds; (3) electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimates of parameters of quantal release, and evaluation of AChR channel kinetics through noise analysis and single channel patch-clamp recordings; (4) mutational analysis of AChR subunits when a kinetic abnormality of AChR is recognized; and (5) collaborative expression studies using genetically engineered mutant AChR when an AChR subunit mutation is identified. The proposed studies are important for diagnosis, treatment and prevention of the CMS; and for gaining additional insights into synaptic function and structure-function relationships of AChR. Moreover, recognition of spontaneous mutations in the EP nicotinic AChR should spur the search for mutations in neuronal nicotinic AChRs and other ligand-gated channels in various neurologic and psychiatric disorders.