Molecular Genetics of Inherited Focal Glomerulerosis

描述（由申请人提供）：本提案的长期目标是了解人类局灶节段性肾小球硬化症（FSGS）的遗传基础。这项工作的基本假设是，了解FSGS的遗传基础将产生相当大的洞察力，不仅对FSGS的遗传形式负责的生物学途径，而且还继发FSGS，以及肾小球硬化和蛋白尿由常见的引发剂，如糖尿病和高血压。该奖项的第一阶段的主要目的是确定19号染色体上的FSGS基因。我们已经确定该基因为ACTN 4，编码细胞骨架蛋白actinin- 4，并已证明显性突变导致肌动蛋白丝结合增加，进行性蛋白尿和肾功能不全。我们已经确定，临床特征，并收集了大量的家庭和个人与FSGS的DNA样本。对这些主题的样本的研究构成了这项工作的基础。 本研究的主要目的有三：首先，我们将对FSGS家族和散发性FSGS患者的ACTN 4、NPHS 2、NPHS 1基因进行突变分析。为了实现这一目标，我们将继续我们的家庭与FSGS，以及零星的成人和儿童病例的确定。突变分析将包括在孟德尔和寡基因遗传模型下评价引起疾病的核苷酸变化。第二，我们将评估孟德尔FSGS/NS基因ACTN 4、NPHS 2、NPHS 1的共同变异在FSGS中的作用。我们将通过定义常见的单核苷酸序列多态性（SNP）来定义FSGS/NS基因ACTN 4、NPHS 1和NPHS 2的单倍型结构。我们将使用关联研究和基于遗传的方法分析这些变异对FSGS表型的贡献。第三，我们的目标是鉴定新的FSGS基因。我们将使用候选基因的方法，通知足细胞遗传学和生物学的最新进展，以确定其他基因突变的家族形式的FSGS。作为一种替代方法，我们将使用全基因组连锁分析来确定新的位点。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the genetic basis of focal segmental glomerulosclerosis (FSGS) in humans. The underlying hypothesis of this work is that understanding the genetic basis of FSGS will yield considerable insight into the biologic pathways responsible not just for inherited forms of FSGS, but also secondary FSGS, as well as glomerulosclerosis and proteinuria resulting from common initiators such as diabetes and hypertension. The major aim of the first period of this award was to identify the FSGS gene on chromosome 19. We have identified this gene as ACTN4, encoding the cytoskeletal protein ctactinin- 4, and have demonstrated that dominant mutations lead to increased binding to actin filaments, progressive proteinuria, and renal insufficiency. We have identified, clinically characterized, and collected DNA samples from a large number of families and individuals with FSGS. The study of samples from these subjects forms the basis of this work. There are three basic aims of this proposal: First, we will perform mutational analysis of ACTN4, NPHS2, NPHS 1 in families with FSGS and patients with sporadic FSGS. Towards this aim, we will continue our ascertainment of families with FSGS, as well as sporadic adult and pediatric cases. Mutational analysis will include evaluation for nucleotide changes causing disease under Mendelian and oligogenic models of inheritance. Second, we will assess the role of common variation in Mendelian FSGS/NS genes ACTN4, NPHS2, NPHS 1 in FSGS. We will define the haplotype structures of FSGS/NS genes ACTN4, NPHS 1, and NPHS2 by definition of common single-nucleotide sequence polymorphisms (SNPs). We will analyze the contribution of these variants to the FSGS phenotype using association studies and inheritance-based approaches. Thirdly, we aim to identify new FSGS genes. We will use a candidate gene approach, informed by recent advances in podocyte genetics and biology, to identify additional genes mutated in familial forms of FSGS. As an alternative approach, we will use a genome-wide linkage analysis to identify new loci.