Translational Research in the Dystrophinopathies

肌营养不良症的转化研究

基本信息

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
项目类别：
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

项目摘要

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.

杜氏肌营养不良症 (DMD) 和贝克尔肌营养不良症 (BMD) 是毁灭性的疾病。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，有 79 个外显子，分布在 2.4 个区域内。百万碱基的基因组序列。大部分基因的缺失约占全部基因的 60% 肌营养不良蛋白突变。其余部分由点突变（主要是过早终止密码子突变）组成，小缺失导致阅读框移动，以及（少于 5%）重复。我们开发了快速、稳健且经济地执行直接序列分析的方法抗肌营养不良蛋白基因的整个编码和调控区域，大大加快了表征非缺失型肌营养不良症患者的突变。使用这种方法，我们建议描述在一大群患者中导致 DMD 和 BMD 的突变，对这些患者进行了标准化和将获得彻底的表型表征。表型/基因型信息将被编译成肌营养不良症登记/数据库。除了基因型与表型的相关性之外，我们还将确定特定突变对 mRNA 加工和翻译的影响及其关系突变背景及其对疾病表型的分子谱。最后我们来测试一下特定错义突变暗示存在尚未鉴定的肌营养不良蛋白的假设具有约束力的伙伴。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目标。尽管我们不建议在以下时间进行治疗试验目前，这项拟议的研究将确定可能成为未来试验候选者的患者群体或在其他机构。