PDF(Pubmed)
Abstract：
Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.
摘要：
神经肌病（NM）是一种罕见的先天性神经肌肉疾病，其特征是肌肉无力和张力减退，电机发育缓慢，呼吸功能下降。至少12个基因的突变,所有的每一种编码蛋白质，这些蛋白质要么是肌肉细丝的组成部分，要么调节其长度和稳定性，与NM有关。星云蛋白(NEB)突变,一种巨大的丝状蛋白位于肌节中，占NM病例的50%以上。目前,对于NEB基因型是否影响星状蛋白功能和NM患者表型,目前仍缺乏了解.此外,目前还缺乏能够发现药物并解决患者当前未满足的治疗需求的可治疗模型.为了开始解决这些差距，在这里，我们描述了与NEB相关的NM的五种新的斑马鱼模型。这些突变体概括了基于NEB的NM的大多数方面，显示存活率大幅下降，有缺陷的肌肉结构,收缩力降低，较短的细丝，肌纤维中存在电子致密结构，和Z盘的增厚。这项研究代表了对星状蛋白突变体等位基因系列的首次广泛研究，因此提供了人类NEB患者潜在基因型-表型相关性的临床前模型的初步检查。它也代表了斑马鱼首次利用一套全面的结果衡量标准，包括分子分析之间的相关性，结构和生物物理研究，和表型结果。因此,它为探索NM病理机制的未来研究提供了丰富的数据来源，以及与NEB相关的NM的治疗鉴定和开发的理想跳板。
