Molecular Genetics of Inherited Focal Glomerulosclerosis

描述(由申请人提供)：最初几个肾病综合征和局灶节段性肾小球硬化(FSGS)基因的识别对了解肾小球功能和疾病具有重要影响。然而，很明显，已知的基因只占这些疾病的一小部分。在这里，我们的目标是进一步阐明FSGS的遗传基础，使用过去11年收集的2500多个个体的数据库。具体地说，我们将对FSGS家族和散发性FSGS患者的已知FSGS基因进行突变分析。我们将继续对患有FSGS的家庭以及零星的成人和儿童病例进行查明。对这些已知的FSGS基因的突变分析将进一步帮助我们了解突变的谱，了解基因/表型的关系，提供更多关于结构和功能的信息，并有助于澄清基因检测的作用。我们还将致力于识别新的FSGS基因。通过全基因组扫描，我们已经确定了几个似乎含有尚未确定的FSGS基因的遗传区域。我们将分析这些疾病相关区域内的基因，以识别与疾病相关的变异。我们将继续在新的、遗传信息丰富的家系中进行额外的全基因组扫描，因为它们被确定了。我们将检验这一假设，即关键足细胞/肾小球基因中罕见的DNA序列变异与FSGS的病因学有关。我们将对300例FSGS病例和300名对照的候选基因进行重新测序，并确定这些基因中罕见的有害变异是否在病例中更常见。我们将在独立的样本集中复制积极的结果。FSGS是慢性肾脏疾病和肾衰竭的一个重要且不断增长的原因。FSGS也是各种基本条件的共同后果。这些研究将有助于了解这种疾病的根本原因。 公共卫生相关性 新的局灶性节段性肾小球硬化(FSGS)基因的识别和已知FSGS基因的进一步遗传学特征将对理解和最终治疗常见形式的肾功能衰竭和肾功能衰竭进展具有重要意义。在不久的将来，FSGS基因缺陷的识别和表征将对诊断工具的发展产生影响。

DESCRIPTION (provided by applicant): Identification of the first several nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) genes has had a significant impact on the understanding of glomerular function and disease. However, It is clear that the known genes account for only a fraction of these diseases. Here our goal is further elucidation of the genetic basis of FSGS, using a database of over 2500 individuals assembled over the past eleven years. Specifically, we will perform mutational analysis of known FSGS genes in families with FSGS and in patients with sporadic FSGS. We will continue our ongoing ascertainment of families with FSGS as well as sporadic adult and pediatric cases. Mutational analysis of these known FSGS genes will further inform our understanding of the spectrum of mutations, inform genotype/phenotype relationships, provide further information regarding structure and function, and help clarify the utility of genetic testing. We will also aim to Identify new FSGS genes. Through genome-wide scans, we have identified several genetic regions that appear to harbor as yet unidentified FSGS genes. We will analyze genes within these disease-associated regions in order to identify disease-associated variation. We will continue to perform additional genome-wide scans in new, genetically informative families as they are ascertained. We will test the hypothesis that rare DNA sequence variants in critical podocyte/glomerulus genes contribute to the etiology of FSGS. We will resequence candidate genes in 300 FSGS cases and 300 controls and determine if rare deleterious variants in these genes are more common in cases. We will replicate positive results in independent sample sets. FSGS is a significant and growing cause of chronic kidney disease and kidney failure. FSGS is also a common consequence of a variety of primary conditions. These studies will help understand the underlying causes of this disease. PUBLIC HEALTH RELEVANCE The identification of new focal segmental glomerulosclerosis (FSGS) genes and further genetic characterization of known FSGS genes will have significant implications for understanding, and ultimately, treating, common forms of renal failure and renal failure progression. In the more immediate future, identification and characterization of FSGS gene defects will have implications for the development of diagnostic tools.