Genetic screening and therapies for nemaline myopathies

项目摘要/摘要 这个项目的长期目标是完成我们对线虫遗传基础的理解。 肌病(NMS)，目的是开发适用于新生儿筛查的快速基因诊断测试 计划，并为NM的常见原因之一开发有效和创新的治疗方法 将通过这样的筛查来识别。线虫性肌病是一种遗传异质性 一组密切相关的先天性肌病，以中度先天性肌病为基础 对严重的骨骼肌无力和肌肉活检发现受影响的肌纤维中的线虫杆状 孩子们。这些条件的统一分子特征是七个已知基因中的六个 编码肌动蛋白细丝的成分，使其成为肌节疾病。尽管广泛 利用作图和候选基因分析进行遗传调查，这是许多病例的遗传基础 仍然不为人知。然而，下一代DNA测序的到来，以及完整的 外显子组和基因组测序使全面的基因研究在快速和经济高效的 举止。将利用整个外显子组测序来完成对一个大井的遗传分析。 根据这些结果，一种特定的DNA捕获芯片将被 旨在方便快速分析NM和相关先天性肌病的所有基因，用于 筛查低张、弱小新生儿。NM缺乏有效的治疗方法，这是他们 发展是缺乏适合于筛选潜在治疗化合物的模型系统。至 为了解决这个问题，斑马鱼模型的骨骼肌动蛋白(ACTA1基因)相关的NM(NEM3)将被 开发和表征，并用于高通量药物筛选，以确定先导化合物与 原发性骨骼肌病患者NM及相关疾病的治疗潜力 肌肉营养不良症。高效、灵敏的新生儿DNA筛查方法的建立 将允许快速和准确的诊断，消除了对更具侵入性和风险的程序的需要 例如肌肉活检，并将允许早期预后确定，高危亲属的携带者检测 以防止未来受影响儿童的出生，并将允许进行最佳的早期医疗管理。 新的治疗化合物和方法的鉴定将为新的临床前试验奠定基础 有朝一日可能会被用来治疗患有这些破坏性神经肌肉疾病的儿童的疗法。 这些进展还将增加我们对基本肌肉生物学的了解，并对我们的 对其他神经肌肉疾病的了解。

PROJECT SUMMARY/ABSTRACT The long-term goals of this project are to complete our understanding of the genetic basis for the nemaline myopathies (NMs) with the aim of developing rapid genetic diagnostic tests suitable for newborn screening programs, and to develop effective and innovative therapies for one of the common causes of NM that would be identified through such screening. The nemaline myopathies are a genetically heterogeneous group of closely related congenital myopathies, defined on the basis of congenital presentation of moderate to profound skeletal muscle weakness and muscle biopsy revealing nemaline rods in myofibers of affected children. The unifying molecular feature of these conditions is that fact that six of the seven known genes encode components of the actin thin filament, making this a disease of the sarcomere. Despite extensive genetic investigations utilizing mapping and candidate gene analysis, the genetic basis for many cases remains unknown. However, the advent of next generation DNA sequencing, and availability of whole exome and genome sequencing makes comprehensive genetic studies feasible in a rapid and cost-effective manner. Whole exome sequencing will be utilized to complete the genetic analysis of a large and well- characterized cohort of NM patients, and on the basis of these results, a specific DNA capture chip will be designed to facilitate rapid analysis of all the genes for NM and related congenital myopathies for use in screening hypotonic and weak newborns. Effective therapies for NM are lacking, and a major hurdle to their development is absence of model systems suitable for screening potential therapeutic compounds. To address this problem, zebrafish models of skeletal actin (ACTA1 gene) related NM (NEM3) will be developed and characterized, and utilized in high throughput drug screens to identify lead compounds with therapeutic potential for NM and related disorders in patients with primary skeletal myopathies and muscular dystrophies. Development of this efficient and sensitive newborn DNA-based screening protocol will allow for rapid and accurate diagnosis, eliminating the need for more invasive and risky procedures such as muscle biopsy, and will allow for early prognostic determinations, carrier testing in at risk relatives to prevent births of future affected children, and will allow for optimal early medical management. Identification of new therapeutic compounds and approaches will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases. These advances will also increase our knowledge of basic muscle biology with implications for our understanding of other neuromuscular diseases.