CONGENITAL MYASTHENIC SYNDROMES

描述：（改编自研究者摘要） 该提案旨在研究先天性心脏病的病理机制 肌无力综合征（CMS）。 CMS是一种高度致残性疾病， 神经肌肉传递的安全限度受到了 一个或多个特定机制。 CMS并不罕见，但 很少被正确诊断或治疗。 适当的形态和 然而，电生理学分析可以识别所涉及的缺陷。 此外，这样的研究可以暗示候选突变蛋白或 基因;例如，电生理鉴定的动力学 AChR的异常是AChR突变的假定证据 亚单位 CMS的方法将通过五个步骤：（1） 临床评估，包括肌电图和抗AchR试验 抗体;（2）形态学评估，包括细胞化学或 乙酰胆碱酯酶、AChR和AChR免疫细胞化学定位 终板（EP）的亚基，每个EP的AChR数量的估计， EP的定量超微结构分析，以及 （3）AChR在连接襞上的密度和分布; 电生理评估，包括常规微电极 EP电位和电流的研究， 量子释放，并通过噪声评估AChR通道动力学 分析和单通道膜片钳记录;（4）突变 当AChR的动力学异常时， （5）利用遗传学方法进行的合作表达研究 当AChR亚基突变被鉴定时，工程化突变AChR。 的 建议的研究对于诊断、治疗和预防都很重要 的CMS;并获得更多的见解突触功能 AChR的结构与功能关系。 此外，承认 EP烟碱AChR的自发突变应该刺激对 神经元烟碱AChRs和其他配体门控通道的突变， 各种神经和精神疾病

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.