GENETICS OF FAMILIAL FOCAL SEGMENTAL GLOMERULOSCLEROSIS

局灶性节段性肾小球硬化(FSGS)是一种原因不明的进行性肾脏疾病，可导致蛋白尿和终末期肾病(ESRD)。目前，我们对节段性肾小球硬化发生的分子机制(S)的认识有限。在目前的应用中，我们建议通过应用位置克隆策略来确定常染色体显性遗传型家族性FSGS的遗传缺陷。我们已经确定了FSGS是孟德尔遗传的具有高外显性的家系。到目前为止，我们已经收集了50个多重、多代的家庭，包含219个受影响的个体，并保存了其中543个家庭成员的DNA，其中包括114个受影响的受试者。在初步研究中，我们建立了与染色体11q21-22的连锁，并证明了家族性FSGS具有遗传异质性。我们计划采取一种系统的方法来研究家族性FSGS，包括：(1)扩大现有的家族性FSGS家系，(2)对非连锁家系进行全基因组作图，以确定遗传异质性的全谱；(3)利用重组和单倍型分析缩小最小候选区域(MCR)；(4)鉴定突变的FSGS基因。最初，我们将缩小11号染色体上已建立连锁的MCR，然后将类似的范例应用于其他FSGS基因座。我们已经在染色体11q21-22上发现了一个横跨MCR的YAC重叠群，它将被证实为该地区表达序列标签位点(EST)、微卫星和基因的定位提供了一个框架。一旦这个框架建立，将构建一个PAC/BAC重叠群，作为产生新的多态标记和候选基因以识别FSGS缺陷的资源。新的候选基因将通过从非嵌合YAC或PAC中直接选择来识别。映射到MCR的候选基因将被完全识别并在受影响的个体中进行突变筛查。这些研究对于我们理解FFSGS的分子基础是至关重要的。来自FFSGS的知识也将有助于更好地了解非遗传性形式FSGS的发病机制，并可能为这种疾病更常见的散发性形式的治疗提供见解。

Focal Segmental Glomerulosclerosis (FSGS) is a progressive disorder of the kidney of unknown etiology that results in proteinuria and End Stage Renal Disease (ESRD). Currently, we have limited insights into the molecular mechanism(s) underlying the development of segmental glomerulosclerosis. In the current application, we propose to determine the genetic defects underlying autosomal dominant forms of familial FSGS by applying positional cloning strategies. We have identified families in which FSGS is inherited as a Mendelian trait with high penetrance. To date, we have collected 50 multiplex, multi-generational families containing 219 affected individuals and banked DNA on 543 of these family members including 114 affected subjects. In preliminary studies, we established linkage to chromosome 11q21-22 and demonstrated that familial FSGS is genetically heterogeneous. We plan to take a systematic approach to study familial FSGS that includes: (1) expanding existing and collecting additional families with familial FSGS, (2) genome wide mapping of unlinked families to define the full spectrum of genetic heterogeneity, (3) narrowing the minimal candidate region (MCR) using recombinant and haplotype analysis, and (4) identifying the mutant FSGS gene. Initially, we will narrow the MCR on chromosome 11 where we have established linkage and later apply a similar paradigm to other FSGS loci. We have identified a YAC contig spanning the MCR on chromosome 11q21-22, which will be verified to provide a framework for mapping of Expressed Sequence Tag Sites (ESTs), microsatellites and genes in the region. Once this framework is established, a PAC/BAC contig will be constructed that will serve as a resource for generating new polymorphic markers and candidate genes to identify the FSGS defect. New candidate genes will be identified using direct selection from non-chimeric YACs or PACs. Candidate gene mapped to the MCR will be fully identified and screened for mutations in affected individuals. These investigations are critical to our understanding of the molecular basis of FFSGS. Knowledge derived from FFSGS will also allow a better understanding of pathogenesis of non-hereditary forms FSGS and may provide insights regarding management of the more common sporadic forms of this disorder.