Genetics of Familial Focal Segmental Glomerulosclerosis

局灶节段性肾小球硬化症（FSGS）是终末期肾病的重要原因。它在黑人患者中特别普遍，数据表明其患病率正在增加。尽管有令人信服的证据表明， 由于FSGS的病因多样，很难在该组中找到致病基因。 综合征因此，我们采取了一种免费的方法来收集罕见的家庭， 孟德尔氏病，寻找可能与更常见的散发性疾病相关的基因。对这些个体基因的研究也为了解这种综合征的病理生理学提供了机会。我们以前曾描述过一个新西兰常染色体显性FSGS家系（FSGS 2）与染色体11 q连锁，最近又在这些家系中发现了遗传突变。 为了进一步表征和阐明家族性FSGS中致病突变的谱，我们提出（1）通过（1a）在已经筛选了457个标记的FSGS家族中建立连锁来鉴定引起FSGS的新基因。已经鉴定了几个用于随访的感兴趣区域，并将通过分型另外的标志物进行检查，以及（Ib）我们将通过精细定位该区域并经由单倍型分析来确定来自特定目标1的任何新鉴定的基因座的MCI，以鉴定关键重组。MCI确定后，将开始候选基因分析。(2)最大化表型数据和选择FSGS家庭的权力，以帮助连锁研究完成确认和扩展。我们将开始我们的确定工作，立即扩大三个家庭从基因组筛选（家庭6543，6510和6524）。根据家族史数据，我们预计自最初确定以来，将从未知类别的个体中的肾脏疾病自然进展中识别出其他受影响的个体。接下来，我们将专注于从我们的FSGS数据集中扩展具有最大连锁潜力的家族。最后，（3）确定杜克FSGS数据集中已知导致遗传性肾小球疾病的基因突变的流行率。我们将在我们的FSGS大家族队列中的所有先证者中对我们最近鉴定的基因NPHS1、NPHS2和ACTN4基因进行测序。这些研究将进一步确定遗传性FSGS的遗传发病机制。在已知引起FSGS的基因中发现的新突变将 加强我们对这种疾病的遗传学和生物学的理解，混乱，利用了我们家庭的全部资源。

Focal and segmental glomerulosclerosis (FSGS) is a significant cause of end-stage renal disease. It is particularly prevalent in black patients and data suggests its prevalence is increasing. Despite compelling evidence for genetic components in sporadic FSGS, it is very difficult to find causative genes in this group due to the diverse etiology of the syndrome. Therefore, we have taken a complimentary approach of collecting families with rare, Mendelian disease, to find genes that may be relevant to the more common sporadic disease. The study of these individual genes also provides an opportunity to understand the pathophysiology of this syndrome. We have previously described linkage to chromosome 11q in a large autosomal dominant FSGS family from New Zealand (FSGS2) and recently discovered the genetic mutatior in these kindred. In an effort to further characterize and elucidate the spectrum of disease-causing mutations in familial FSGS, we propose to (1) Identify novel genes that cause FSGS by (la) establishing linkage in FSGS families already screened for 457 markers. Several regions of interest for follow-up have been identified and will be examined by typing additional markers and (lb) we will define the MCI for any newly identified loci from specific aim 1 by fine-mapping the region and via haplotype analysis to identify critical recombinations. After the MCI is defined candidate gene analysis will commence. (2) Maximize phenotypic data and power of selected FSGS families to aid linkage studies by completing ascertainment and expansion. We will begin our ascertainment efforts immediately by expanding the three families from the genomic screen (families 6543, 6510 and 6524). Based on family history data, we anticipate that additional affected individuals will be identified from the natural progression of kidney disease in individuals from the unknown category since original ascertainment. We will focus next on expanding families from our FSGS dataset that have the greatest linkage potential. Lastly, (3) Determine the prevalence of mutations in genes that are known to cause inherited glomerular diseases in the Duke FSGS dataset. We will sequence our recently identified gene, NPHS1, NPHS2 and ACTN4 genes in all probands in our large cohort of families with FSGS. These studies will further define the genetic pathogenesis of inherited FSGS. New mutations found in the genes known to cause FSGS will enhance our understanding of the genetics and biology of thi., disorder, takin 9 advantage of our entire resource of families.