MOLECULAR STUDIES IN AUTOSOMAL DOMINANT LIMB GIRDLE MUSCULAR DYSTROPHY(LGMD)

常染色体显性肢体带状肌营养不良症（LGMD）的分子研究

• 批准号: 6444652
• 负责人: JEFFERY Marvin VANCE
• 金额: $ 20.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444652
• 关键词: artificial chromosomes; autosomal dominant trait; chromosomes; clinical research; cytogenetics; family genetics; gene mutation; genetic polymorphism; genetic screening; genotype; hereditary motor and sensory neuropathy; human data; human genetic material tag; human subject; linkage mapping; molecular cloning; molecular pathology; muscular dystrophy; neurogenetics; nucleic acid repetitive sequence; nucleic acid sequence; phenotype

Limb Girdle Muscular Dystrophy is major form of muscular dystrophy affecting both adults and children. The autosomal recessive LGMD have made major progress in understanding these disorders through positional cloning and candidate protein analysis. We propose to take a similar approach to the autosomal dominant form of this disease. Through the previous funding period we have collected 23 autosomal dominant families (LGMD1) comprising 795 individuals. From this group we have previously linked a large family to chromosome 5 (LGMD1a). Recently, we have identified another LGMD1 locus on chromosome 7q36 (LGMD1D). In collaboration with Dr. Carol Westbrook, we have previously established a 2 megabase YAC/BAC contig across the chromosome 5 LGMD1A region and have screened 33 ESTs lying within this region for muscle expression. Currently, we are characterizing and evaluating positive clones for potential mutations. We propose to continue to narrow the LGMD1A minimal candidate region and perform candidate gene analysis using direct selection if needed, to identify the gene defect. Once the LGMD1A gene defect is identified, we will begin mapping the LGMD1D region on chromosome 7q36 to identify this gene defect. Physical mapping for the chromosome 7q36 region will be done in conjunction with Dr. Eric Green, who is responsible for forming contigs on chromosome 7 for the sequencing initiative of the chromosome for Washington University. Three large YAC contigs already span the current LGMD1D region, with two gaps. We will also utilize direct selection for this analysis but we anticipate sequence data to be available to assist in identifying the LGMD1D gene. Once the LGMD1A or LGMD1D gene is identified, we will work with our consultant Dr. Lou Kunkel to evaluate the function of the protein, assess the extent of mutations in small and isolated LGMD cases, and evaluate any genotype/phenotype correlations.

肢体腰围肌营养不良是影响成年人和儿童的肌肉营养不良的主要形式。常染色体隐性LGMD通过位置克隆和候选蛋白分析在理解这些疾病方面取得了重大进展。我们建议采取类似的方法来对这种疾病的常染色体显性形式。在过去的资金期间，我们收集了23个常染色体显性遗传（LGMD1），其中包括795个人。从该组中，我们以前已经将一个大家庭与5号染色体（LGMD1A）联系起来。最近，我们在7q36染色体（LGMD1D）上确定了另一个LGMD1基因座。与Carol Westbrook博士合作，我们以前曾在5 LGMD1A染色体上建立了2兆瓦的YAC/BAC重叠群，并筛选了位于该区域内的33个EST，以进行肌肉表达。当前，我们正在表征和评估潜在突变的正质克隆。我们建议继续缩小LGMD1A最小候选区域，并在需要时使用直接选择进行候选基因分析，以识别基因缺陷。一旦确定了LGMD1A基因缺陷，我们将开始映射7q36染色体上的LGMD1D区域，以识别该基因缺陷。第7q36染色体区域的物理图将与埃里克·格林（Eric Green）博士一起进行，他负责在华盛顿大学的染色体测序倡议上形成7号染色体的重叠群。三个大的YAC重叠群已经跨越了当前的LGMD1D区域，并有两个间隙。我们还将在此分析中使用直接选择，但是我们预计将可以使用序列数据来帮助识别LGMD1D基因。一旦确定了LGMD1A或LGMD1D基因，我们将与顾问Lou Kunkel博士一起评估蛋白质的功能，评估小型和分离的LGMD病例中突变的程度，并评估任何基因型/表型相关性。