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

基本信息

项目摘要

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):先天性肾脏异常(CAKUT)的新基因和病理机制。慢性肾脏疾病(CKD)是危害人类健康最严重的疾病之一,需要透析或肾移植才能生存。先天性肾和尿路异常(ckut)是儿童CKD最常见的病因,约占所有病例的50%。我们之前通过定位克隆确定了2个新的显性单基因导致CAKUT (Ruf PNAS 101:890, 2004; Hoskins AJHG 80:800, 2007)。现在,我们从一个来自456个不同家庭的多种族CAKUT儿童队列中收集了基因组DNA和临床数据,并通过总基因组纯合性图谱生成了初步数据,证明了在同胞和非综合征性CAKUT的单个病例中存在隐性单基因位点。我们还建立了一种新的外显子组捕获技术,通过连续大规模测序来鉴定新的CAKUT单基因病因。在20个兄弟姐妹中,我们定位了1个新的位点和几个假定的位点,它们是纯合的,作为未知基因的致病隐性突变的强候选位点。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,包括隐性和显性基因,将代表CAKUT的新原因。我们现在将采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鉴定和功能表征新的cakut -致病基因。我们将努力实现以下目标:通过纯合子作图、外显子捕获和大规模(LS)测序,在具有血统纯合子的家庭中确定新的隐性原因。2. 通过2.1M全人类外显子组捕获和LS测序确定新的显性原因。3. 在斑马鱼模型中对新发现的CAKUT基因进行功能表征。

项目成果

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FRIEDHELM HILDEBRANDT其他文献

FRIEDHELM HILDEBRANDT的其他文献

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{{ truncateString('FRIEDHELM HILDEBRANDT', 18)}}的其他基金

Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
  • 批准号:
    10047547
  • 财政年份:
    2020
  • 资助金额:
    $ 38.19万
  • 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
  • 批准号:
    10441350
  • 财政年份:
    2020
  • 资助金额:
    $ 38.19万
  • 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
  • 批准号:
    10237944
  • 财政年份:
    2020
  • 资助金额:
    $ 38.19万
  • 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
  • 批准号:
    10652318
  • 财政年份:
    2020
  • 资助金额:
    $ 38.19万
  • 项目类别:
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:
    8318885
  • 财政年份:
    2010
  • 资助金额:
    $ 38.19万
  • 项目类别:
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:
    8630181
  • 财政年份:
    2010
  • 资助金额:
    $ 38.19万
  • 项目类别:
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:
    8105180
  • 财政年份:
    2010
  • 资助金额:
    $ 38.19万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 38.19万
  • 项目类别:
Exon capture and large-scale sequencing for disease-cause identification, early d
外显子捕获和大规模测序用于疾病原因识别、早期诊断
  • 批准号:
    7819207
  • 财政年份:
    2009
  • 资助金额:
    $ 38.19万
  • 项目类别:
Exon capture and large-scale sequencing for disease-cause identification, early d
外显子捕获和大规模测序用于疾病原因识别、早期诊断
  • 批准号:
    7936906
  • 财政年份:
    2009
  • 资助金额:
    $ 38.19万
  • 项目类别:

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