New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)

先天性肾脏异常（CAKUT）的新基因和病理机制

• 批准号: 8507725
• 负责人: FRIEDHELM HILDEBRANDT
• 金额: $ 34.69万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507725
• 关键词: Accounting; Animal Model; Biological Models; Candidate Disease Gene; Child; Chronic Kidney Failure; Clinical Data; Congenital Abnormality; Consensus; DNA; Data; Databases; Diagnostic; Dialysis procedure; Disease; Exons; Family; Gene Mutation; Genes; Genome; Genomics; Health; Human; Kidney; Kidney Transplantation; Large-Scale Sequencing; Lead; Maps; Methods; Modeling; Molecular Genetics; Mutation; Physiological; Preclinical Drug Evaluation; Prophylactic treatment; Recruitment Activity; Role; Shipping; Ships; Single-Gene Defect; Testing; Urinary tract; Zebrafish; animal model development; cohort; exome; mouse model; new technology; novel; novel strategies; positional cloning; public health relevance; zebrafish development

DESCRIPTION (provided by applicant): New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT). Chronic kidney diseases (CKD) take one of the highest tolls on human health, requiring dialysis or kidney transplantation for survival. Congenital abnormalities of the kidney and urinary tract (CAKUT) constitute the most frequent cause of CKD in children, accounting for ~50% of all cases. We identified previously, by positional cloning, 2 novel dominant single-gene causes of CAKUT (Ruf PNAS 101:890, 2004; Hoskins AJHG 80:800, 2007). We, now, recruited genomic DNA and clinical data in a multi-ethnic cohort of children with CAKUT from 456 different families, and generated preliminary data by total genome homozygosity mapping that demonstrate the presence of recessive single-gene loci in sib ships and single cases with non-syndromic CAKUT. We also established a new technology of exome capture with consecutive large-scale sequencing for the identification of novel single-gene causes of CAKUT. In 20 sib ships we mapped 1 new locus and several putative loci, which are homozygous by descent, as strong candidate loci for causative recessive mutations in unidentified genes. From these data and from animal models of CAKUT we hypothesize that single-gene mutations in many distinct unidentified genes, both recessive and dominant, will represent novel causes of CAKUT. We will now employ our newly established method of homozygosity mapping with exon capture and consecutive large- scale sequencing to identify and functionally characterize novel CAKUT-causing genes. We will pursue the following aims: 1. Identify novel recessive causes of CAKUT by homozygosity mapping, exon capture, and large-scale (LS) sequencing in families with homozygosity by descent. 2. Identify novel dominant causes of CAKUT by 2.1M Whole Human Exome Capture and LS sequencing. 3. Functionally characterize the newly identified CAKUT genes in zebrafish models. PUBLIC HEALTH RELEVANCE: Congenital abnormalities of the kidney and urinary tract (CAKUT) account for about ~50% of chronic kidney disease in children. No prophylaxis or curative treatment is available. Although many forms of CAKUT are very likely caused by single-gene defects, only few causative genes have been identified so far. We recently established a new approach of homozygosity mapping, exon capture and large-scale sequencing for identification of new CAKUT-causing genes. We will apply these new approaches to a worldwide cohort of 456 families with CAKUT, which we have recruited. The identification of new single-gene causes of SRNS will: i) lead to identification of novel single-genes causes of CAKUT; ii) introduce the new technologies of exon capture and large-scale sequencing into the diagnostics of CAKUT; iii) permit early, unequivocal molecular genetic diagnostics; iv) help unravel the disease mechanisms of CAKUT; v) allow detailed mechanistic studies of the pathomechanisms of CAKUT in zebrafish models; vi) permit development of zebrafish model systems for high-throughput drug screening for this disease.

描述(申请人提供)：先天性肾脏畸形的新基因和发病机制(CAKUT)。慢性肾脏疾病(CKD)是影响人类健康的最高费用之一，需要透析或肾移植才能生存。先天性肾脏和尿路异常(CAKUT)是儿童CKD最常见的病因，约占所有病例的50%。我们先前通过定位克隆鉴定了2个新的CAKUT显性单基因病因(Ruf PNAS 101：890,2004；Hoskins AJHG 80：800,2007)。现在，我们收集了来自456个不同家庭的CAKUT儿童的多民族队列的基因组DNA和临床数据，并通过总基因组纯合性图谱生成初步数据，证明在同胞和非综合征CAKUT单个病例中存在隐性单基因座位。我们还建立了一种新的外显子组捕获和连续大规模测序的新技术，用于鉴定CAKUT的新的单基因病因。在20个同胞中，我们定位了一个新的基因座和几个推测的基因座，它们是血统纯合的，作为未知基因致病隐性突变的强烈候选基因座。根据这些数据和CAKUT的动物模型，我们假设许多不同的未知基因的单基因突变，无论是隐性的还是显性的，都将代表CAKUT的新原因。我们现在将使用我们新建立的外显子捕获纯合子作图和连续大规模测序的方法来识别和表征新的导致CAKUT的基因。我们将致力于以下目标：1.通过纯合子作图、外显子捕获和血统纯合家系的大规模(LS)测序，确定CAKUT的新的隐性原因。2.通过2.1M全人类外显子组捕获和LS测序鉴定CAKUT的新的显性原因。3.斑马鱼模型中新发现的CAKUT基因的功能特征。 公共卫生相关性：先天性肾脏和尿路异常(CAKUT)约占儿童慢性肾脏疾病的50%。目前还没有预防或根治的方法。虽然许多形式的CAKUT很可能是由单基因缺陷引起的，但到目前为止只有很少的致病基因被鉴定出来。我们最近建立了一种新的纯合子定位、外显子捕获和大规模测序的方法来鉴定新的CAKUT致病基因。我们将把这些新方法应用于我们招募的全球456个患有CAKUT的家庭。对SRNS新的单基因病因的鉴定将：i)导致确定CAKUT的新的单基因病因；ii)将外显子捕获和大规模测序的新技术引入CAKUT的诊断；iii)实现早期、明确的分子遗传学诊断；iv)有助于揭示CAKUT的发病机制；v)允许在斑马鱼模型中对CAKUT的发病机制进行详细的机制研究；vi)允许建立斑马鱼模型系统，用于该疾病的高通量药物筛选。