AUTOSOMAL DOMINANT FOCAL SEGMENTAL GLOMERULOSCLEROSIS

描述（改编自应用程序） 局灶节段性肾小球硬化（FSGS）是一种病理实体， 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，对这一问题的认识有限。 FSGS发展的分子机制。的目的 一项建议是研究与遗传性疾病相关的分子缺陷， 使用定位克隆策略的家族性FSGS的形式。到目前为止， 确定了50多个多重，多代家庭的证据， 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名受影响者。在 初步研究，我们建立了与染色体11 q21 -22的连锁， 大，7代，399成员亲属来自新西兰（家庭6530），也 表明常染色体显性FSGS是遗传异质性的。在这 这项研究，这种疾病将进一步表征家庭6530通过 （1）缩小最小候选区域（MCR）， 所有可用的多态性标记和单倍型分析，以及（2）鉴定 候选基因和最终与FSGS相关的突变， 家人在MCR被缩小到最小可能的区域后， 人工染色体（YAC）重叠群将被构建。有几个（YAC） 已经鉴定的跨越感兴趣区域的重叠群， 染色体11 q21 -22，并且是可商购的。YAC重叠群将 为PI人工染色体（PAC）和细菌染色体的排序提供了一个框架。 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），微卫星和基因的MCR。的 在这个家族中寻找突变的FSGS基因将首先尝试通过一个 候选基因的方法，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 方法不成功。这些调查对我们的 了解家族性FSGS的分子基础。导出的信息 这项研究还将使人们更好地了解 FSGS的非遗传性形式，并可能提供有关管理的见解， 更常见的特发性疾病

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.