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

肢带型肌营养不良症是影响成人和儿童的肌营养不良症的主要形式。通过定位克隆和候选蛋白分析，常染色体隐性遗传LGMD在了解这些疾病方面取得了重大进展。我们建议对这种疾病的常染色体显性形式采取类似的方法。通过上一个资助期，我们收集了23个常染色体显性遗传家族（LGMD 1），包括795个个体。从这个组中，我们以前将一个大家族与5号染色体（LGMD 1a）联系起来。最近，我们在染色体7 q36上发现了另一个LGMD 1基因座（LGMD 1D）。与Carol Westbrook博士合作，我们先前已经在5号染色体LGMD 1A区域建立了一个2兆碱基的YAC/BAC重叠群，并筛选了33个位于该区域内的肌肉表达EST。目前，我们正在表征和评估潜在突变的阳性克隆。我们建议继续缩小LGMD 1A最小候选区域，并在必要时使用直接选择进行候选基因分析，以确定基因缺陷。一旦确定LGMD 1A基因缺陷，我们将开始定位染色体7 q36上的LGMD 1D区域以确定该基因缺陷。将与Eric绿色博士一起完成染色体7 q36区域的物理作图，该博士负责在7号染色体上形成重叠群，用于华盛顿大学的染色体测序计划。三个大的YAC重叠群已经跨越了目前的LGMD 1D区域，有两个缺口。我们还将利用直接选择进行此分析，但我们预计序列数据可用于帮助识别LGMD 1D基因。一旦确定LGMD 1A或LGMD 1D基因，我们将与我们的顾问Lou Kunkel博士合作，评估蛋白质的功能，评估小型和孤立LGMD病例的突变程度，并评估任何基因型/表型相关性。

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.