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: 7940309
• 负责人: FRIEDHELM HILDEBRANDT
• 金额: $ 38.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940309
• 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; abstracting; 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（由申请人提供）：肾脏先天性异常的新基因和病理学（Cakut）。慢性肾脏疾病（CKD）接受人类健康的最高通行费之一，需要透析或肾脏移植才能生存。肾脏和尿路（Cakut）的先天性异常构成儿童CKD的最常见原因，占所有病例的约50％。我们先前通过位置克隆确定了2种新型的Cakut的主要单基因原因（RUF PNAS 101：890，2004; Hoskins AJHG 80：800，2007）。现在，我们在来自456个不同家族的Cakut的多民族群体中招募了基因组DNA和临床数据，并通过总基因组纯合绘制图生成了初步数据，这些数据证明了在SIB船中存在隐性单基因基因座，并与非同步cakut的单个病例中存在。我们还建立了一项新技术，并通过连续的大规模测序来识别新型的单基因原因。在20艘SIB舰船中，我们绘制了1个新的基因座和几个假定的基因座，它们是纯合的下降，作为在身份不明基因中的致病隐性突变的强大候选基因座。从这些数据和Cakut的动物模型中，我们假设许多不同的不明基因中的单基因突变（无论是隐性和主导性）将代表Cakut的新原因。现在，我们将采用新建立的纯合性映射方法，并连续捕获和连续的大规模测序来识别并在功能上表征新型Cakut引起的基因。我们将追求以下目的：1。通过纯合性映射，外显子捕获和大规模（LS）测序确定新的隐性原因，以血后代的纯合性。 2。通过2.1m全人类外显组捕获和LS测序确定Cakut的新型主要原因。 3。在功能上表征了斑马鱼模型中新鉴定的Cakut基因。 公共卫生相关性：肾脏和尿路（Cakut）的先天性异常（Cakut）约占儿童慢性肾脏病的约50％。没有预防或治疗治疗。尽管许多形式的cakut很可能是由单基因缺陷引起的，但到目前为止，只有很少的因果基因被发现。最近，我们建立了一种纯合性映射，外显子捕获和大规模测序的新方法，用于鉴定新的Cakut引起的基因。我们将把这些新方法应用于我们已招募的456个与Cakut家庭组成的全球人群。 SRN的新单基因原因的识别将：i）导致识别新型的单基因原因； ii）将外显子捕获和大规模测序的新技术引入Cakut的诊断； iii）允许早期，明确的分子遗传诊断； iv）帮助揭开卡库特的疾病机制； v）允许对斑马鱼模型中Cakut的病理机理的详细机械研究； vi）允许开发用于该疾病的高通量药物筛查的斑马鱼模型系统。