Molecular Genetics of Inherited Focal Glomerulerosis

描述（由申请人提供）：本申请的长期目标是了解人类局灶节段性肾小球硬化（FSGS）的遗传基础。这项工作的潜在假设是，了解FSGS的遗传基础将使我们对遗传形式的FSGS，以及继发性FSGS，以及由糖尿病和高血压等常见发起者引起的肾小球硬化和蛋白尿的生物学途径有更深入的了解。该奖项第一期的主要目的是鉴定19号染色体上的FSGS基因。我们已经确定该基因为ACTN4，编码细胞骨架蛋白actitinin - 4，并且已经证明显性突变导致肌动蛋白细丝结合增加，进行性蛋白尿和肾功能不全。我们已经鉴定、临床鉴定并收集了大量患有FSGS的家庭和个人的DNA样本。对这些主题的样本的研究构成了这项工作的基础。

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.