Translational Research in the Dystrophinopathies

描述(申请人提供)：Duchenne肌营养不良症(DMD)和Becker肌营养不良症(BMD)是毁灭性的疾病。这两种基因都与营养不良蛋白基因的突变有关，该基因是一个巨大的基因，有79个外显子，分布在240万个基因组序列中。该基因的大部分缺失约占所有营养不良蛋白突变的60%。其余的包括点突变(主要是过早的终止密码子突变)，导致阅读框架移位的微小缺失，以及(不到5%)重复。我们已经开发了一种方法，可以快速、可靠和经济地对dystrophin基因的整个编码和调节区进行直接序列分析，大大加快了非缺失型营养不良症患者突变的特征。使用这种方法，我们建议在一大群患者中确定导致DMD和BMD的突变的特征，从这些患者中将获得标准化和彻底的表型特征。表型/基因型信息将在营养不良症登记处/数据库中汇编。除了基因与表型的相关性外，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图谱与疾病表型的关系。最后，我们将测试这一假设，即特定的错义突变意味着存在迄今尚未表征的dystrophin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，并可能为治疗提供新的靶点。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在这里或其他机构进行任何未来试验的患者队列。

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.