Translational Research in the Dystrophinopathies

肌营养不良症的转化研究

• 批准号: 7588737
• 负责人: KEVIN M FLANIGAN
• 金额: $ 82.22万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588737
• 关键词: Accounting; Becker Muscular Dystrophy; Binding; Biopsy; Cataloging; Catalogs; Cell Line; Clinic; Clinical; Clinical Trials; Code; Communities; Data; Databases; Disease; Duchenne muscular dystrophy; Dystrophin; Epitope Mapping; Evaluation; Exons; Future; Gene Proteins; Gene Rearrangement; Genes; Genetic Counseling; Genomics; Genotype; Goals; Gold; Immunoblot Analysis; Individual; Institution; Iowa; Laboratories; Light; Messenger RNA; Methodology; Methods; Missense Mutation; Molecular; Molecular Diagnosis; Molecular Profiling; Muscle; Muscular Dystrophies; Mutation; Mutation Analysis; Myoblasts; Natural History; Needle biopsy procedure; Nonsense Codon; Nucleic Acid Regulatory Sequences; Ohio; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Philadelphia; Point Mutation; Process; Proteins; RNA Splicing; Reading Frames; Registries; Research; Sequence Analysis; Site; Supportive care; Techniques; Terminator Codon; Testing; Tissues; Translation Process; Translational Research; Translations; Universities; Update; Utah; Washington; base; cohort; database of Genotypes and Phenotypes; disease phenotype; gene replacement; genetic analysis; improved; molecular phenotype; novel; protein function; research study; treatment trial

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.

Duchenne肌肉营养不良（DMD）和Becker肌肉营养不良（BMD）是毁灭性疾病。 两者都与肌营养不良蛋白基因的突变有关，这是一个巨大的基因，具有79个外显子的分布在2.4上 百万基因组序列基碱基。大部分基因的删除占所有基因的60％ 肌营养不良蛋白突变。其余部分由点突变（主要是过早的停止密码子突变）组成， 小删除导致阅读框架的变化，并且（不到5％）重复。 我们已经开发了快速，健壮和经济执行直接序列分析的方法论 在肌营养不良基因的整个编码和调节区域中，大大加快了表征 非骨骼肌营养不良患者的突变。使用这种方法，我们建议表征 在大量患者中负责DMD和BMD的突变，从中标准化和 将获得彻底的表型表征。表型/基因型信息将在 肌营养不良注册表/数据库。除了基因型与表型的相关性外，我们还将 确定特定突变对mRNA处理和翻译的影响以及关系 突变的环境及其结果对疾病表型的分子谱。最后，我们将测试 特定错义突变意味着存在尚未表征的肌营养不良蛋白的假设 约束伙伴。 我们的患者突变目录将确定影响疾病发病机理的分子途径， 并可能提出新的治疗目标。尽管我们不建议在 目前，这项拟议的研究将确定可能是以后试验的候选人的患者队列 或其他机构。