Translational Research in the Dystrophinopathies

描述（由申请人提供）：杜氏肌营养不良症（DMD）和贝克尔肌营养不良症（BMD）是破坏性疾病。两者都与肌营养不良蛋白基因的突变有关，肌营养不良蛋白基因是一个巨大的基因，有79个外显子，分布在240万个碱基的基因组序列中。大部分基因的缺失占所有肌营养不良蛋白突变的60%左右。其余由点突变（主要是提前终止密码子突变）、导致阅读框移位的小缺失和（小于5%）重复组成。我们已经开发了快速，稳健，经济地进行直接序列分析的整个编码和调控区的肌营养不良蛋白基因的方法，大大加快非缺失型肌营养不良蛋白病患者的突变的表征。使用这种方法，我们建议在一个大的患者队列，从他们的标准化和彻底的表型表征，DMD和BMD的突变负责的特点。表型/基因型信息将在肌营养不良症登记/数据库中进行汇编。除了基因型与表型的相关性，我们还将确定特定突变对mRNA加工和翻译的影响，以及突变背景及其产生的分子谱与疾病表型的关系。最后，我们将测试的假设，即特定的错义突变意味着存在尚未表征的抗肌萎缩蛋白结合伙伴。我们的患者突变目录将确定影响疾病发病机制的分子途径，并可能提出新的治疗靶点。虽然我们目前不建议进行治疗试验，但这项拟议的研究将确定可能成为未来在这里或其他机构进行任何试验的候选人的患者队列。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are devastating disorders. Both are associated with mutations in the dystrophin gene, a huge gene with 79 exons spread over 2.4 million bases of genomic sequence. Deletions of large portions of the gene account for around 60% of all dystrophin mutations. The remainder consist of point mutations (primarily premature stop codon mutations), small deletions resulting in shift of the reading frame, and (in less than 5%) duplications. We have developed the methodology to rapidly, robustly, and economically perform direct sequence analysis of the entire coding and regulatory regions of the dystrophin gene, greatly expediting the characterization of mutations in non-deleted dystrophinopathy patients. Using this methodology, we propose to characterize the mutations responsible for DMD and BMD in a large cohort of patients, from whom a standardized and thorough phenotypic characterization will be obtained. Phenotype/genotype information will be compiled in a dystrophinopathy registry/database. In addition to correlation of the genotype to the phenotype, we will determine the effect that specific mutations have on mRNA processing and translation, and the relationship of both the mutations context and its resultant molecular profile to disease phenotype. Finally, we will test the hypothesis that specific missense mutations imply the presence of as-yet uncharacterized dystrophin binding partners. Our catalogue of patient mutations will identify molecular pathways which influence disease pathogenesis, and may suggest novel targets for treatment. Although we do not propose to perform treatment trials at present, this proposed study will identify cohorts of patients who may be candidates for any future trials here or at other institutions.