AUTOSOMAL DOMINANT FOCAL SEGMENTAL GLOMERULOSCLEROSIS

说明(改编自应用程序) 局灶性节段性肾小球硬化(FSGS)是一种未知的病理实体 以蛋白尿、肾病综合征和进行性肾病为特征的病因学 肾功能丧失。目前，对这一问题的见解有限 FSGS发生的分子机制。这样做的目的是 建议调查与遗传性疾病相关的分子缺陷 使用位置克隆策略的家族性FSGS的形式。到目前为止，我们有 确认了50多个多代、多代家庭，有证据表明 FSGS的孟德尔遗传(常染色体显性和隐性)。我们有 收集并储存了543名个体的DNA，其中包括114名受影响的人。在……里面 初步研究，我们在一个染色体上建立了与11q21-22的连锁， 大型，7代，399名成员，来自新西兰(家庭6530)，还 证明常染色体显性FSGS在遗传上是异质性的。在这 研究表明，这种疾病将在6530个家庭中进一步表现出来 遵循特定目标；(1)使用以下方法缩小最小候选区域 所有可用的多态标记和单倍型分析以及(2)鉴定 候选基因和最终与FSGS相关的突变 一家人。在MCR被缩小到可能的最小区域后，酵母 将构建人工染色体(YAC)重叠群。有几个(YAC) 已经确定的跨越感兴趣区域的重叠群 染色体11q21-22，可以在商业上买到。YAC重叠群将 为PI人工染色体(PAC)和细菌的排序提供框架 人工染色体(BAC)重叠群PAC和BAC将依次用于映射 表达序列标签(EST)、微卫星和MCR中的基因。这个 在这个家族中寻找突变的FSGS基因将首先通过一个 候选基因方法，并随后通过直接鉴定新的 使用直接选择和外显子捕获的候选基因，如果候选基因 方法是不成功的。这些调查对我们的 了解家族性FSGS的分子基础。信息源自 这项研究也将使我们更好地了解糖尿病的发病机制。 非遗传性形式的FSGS，并可提供有关FSGS的管理的见解 这种疾病更常见的特发性形式。

DESCRIPTION (adapted from the application) Focal segmental glomerulosclerosis (FSGS) is a pathological entity of unknown etiology characterized by proteinuria, nephrotic syndrome and the progressive loss of renal function. Currently, there are limited insights into the molecular mechanisms underlying the development of FSGS. The objective of this proposal is to investigate the molecular defects associated with an inherited form of familial FSGS using positional cloning strategies. To date, we have identified over 50 multiplex, multi-generation families with evidence of Mendelian inheritance of FSGS (both autosomal dominant and recessive). We have collected and banked DNA on 543 individuals, including 114 affecteds. In preliminary studies, we established linkage to chromosome 11q21-22 in one, large, 7 generation, 399 member kindred from New Zealand (family 6530) and also demonstrated that autosomal dominant FSGS is genetically heterogeneous. In this study, this disorder will be further characterized in family 6530 through the following Specific Aims; (1) narrowing the minimal candidate region (MCR) using all available polymorphic markers and haplotype analysis and (2) identifying candidate genes and ultimately the mutation associated with FSGS in this family. After the MCR is narrowed to the smallest possible region, a yeast artificial chromosome (YAC) contig will be constructed. There are several (YAC) contigs that have been identified which span the region of interest on chromosome 11q21-22 and which are commercially available. The YAC contig will provide a framework for ordering PI artificial chromosome (PAC) and bacterial artificial chromosome (BAC) contigs. PACs and BACs will in turn be used to map expressed sequence tags (ESTs), microsatellites and genes in the MCR. The search for the mutant FSGS gene in this family will first be attempted via a candidate gene approach and subsequently through direct identification of new candidate genes using direct selection and exon trapping, if the candidate gene approach is unsuccessful. These investigations are critical to our understanding of the molecular basis of familial FSGS. Information derived from this research will also allow a better understanding of the pathogenesis of nonhereditary forms of FSGS and may provide insights regarding management of the more common idiopathic forms of this disorder.