Genomics of mammalian posterior urethral valves

哺乳动物后尿道瓣膜的基因组学

• 批准号: 9427411
• 负责人: Simone Sanna-Cherchi
• 金额: $ 60.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9427411
• 关键词: Affect; Alleles; Apoptosis; Architecture; Biological Assay; Candidate Disease Gene; Child; Child Care; Childhood; Clinical; Complex; Coupled; DNA Microarray Chip; DNA Resequencing; Data; Data Set; Defect; Development; Diagnosis; Diagnostic; Dialysis procedure; Disease; Disease model; Duct (organ) structure; Embryo; End stage renal failure; Epidemiology; Etiology; Failure; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic Models; Genetic Predisposition to Disease; Genomics; Genotype; Human; Human Genetics; Hypospadias; Link; Lower urinary tract; Middle Lobe Syndrome; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Nucleotides; Obstruction; Parents; Pathogenicity; Pathway interactions; Patients; Phenotype; Pilot Projects; Play; Point Mutation; Role; SNP genotyping; Severity of illness; Structure of paramesonephric duct; Susceptibility Gene; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcript; Transplantation; Urethra; Urology; Variant; Vas deferens structure; Work; base; cohort; cost; cost effective; data modeling; design; dosage; exome; exome sequencing; fitness; gene discovery; genetic variant; improved; insight; male; malformation; mortality; mouse model; mutant; novel; personalized care; pressure; rare variant; segregation; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; validation studies

Posterior urethral valves (PUV) are the major cause of lower urinary tract obstruction in male children and account for 17% of pediatric end-stage renal disease. Despite the severity of the disease and its impact on mortality and morbidity, the molecular basis of this condition is largely unknown, resulting in suboptimal diagnostic and therapeutic strategies. The epidemiology of the disease, characterized by high selective pressure versus a phenotype with low fitness, suggests that dominant de novo mutations or recessive inheritance play a major role in disease determination. This proposal represents the natural continuation of a Pilot project from our O'Brien Center of Urology and aims at the identification of the genetic susceptibility factors for posterior urethral valves (PUV). Our central hypothesis is that rare variants with large effect size on the phenotype underlie the genetic architecture of PUV, and that combining high-throughput genomic studies with analysis of two mouse models of disease will lead to the identification of novel disease genes. Our preliminary data using exome and geneome sequencing, CNV analysis, and functional modeling in vertebrate strongly indicate that we can successfully identify novel genomic variants with large effect size, even in scenario of complex genetic architecture and high genetic heterogeneity. In particular, by studying CNVs in a large cohort of PUV patient, we identified different novel candidate genes for PUV and lower urinary tract malformation. We next demonstrated that mouse transcript dosage of one of these gene candidates, Tbx6, results in highly penetrant maldevelopment and lack of canalization of urethra similar to human PUV. Simultaneously, we have identified a set of genes that are disregulated in mouse mutants lacking Sall1, a transcription factor that when mutated in humans causes Townes-Brocks Syndrome (TBS), a clinical entity characterized by different malformations, including anorectal defects, PUV, and hypospadias. We now propose to extend our sequencing effort to additional 200 PUV trios, and to replicate findings in a large cohort of patients to identify novel genes. We will also characterize the lower urinary tract defects of Sall1 and Tbx6 and generate whole transcriptome datasets to identify downstream targets and facilitate gene identification in humans. This study is designed to solve the molecular etiology of PUV, to improve diagnosis and individualized care for children affected by this severe condition, and to identify pathways that can be amenable to therapeutic interventions.

后尿道瓣膜（PUV）是男性儿童下尿路梗阻的主要原因， 占儿童终末期肾病的17%。尽管疾病的严重性及其对 死亡率和发病率，这种情况的分子基础在很大程度上是未知的， 诊断和治疗策略。该病的流行病学特点是高选择性 压力与适应性低的表型，表明显性从头突变或隐性 遗传在疾病决定中起主要作用。 该提案代表了我们奥布莱恩泌尿外科中心试点项目的自然延续， 目的：探讨后尿道瓣膜（PUV）的遗传易感因素。我们的中央 假设是，对表型具有大效应量的罕见变异是以下遗传结构的基础： 结合高通量基因组研究和两种小鼠疾病模型的分析， 导致新的疾病基因的鉴定。我们使用外显子组和基因组测序的初步数据， CNV分析和脊椎动物的功能建模强烈表明，我们可以成功地识别新的 即使在复杂的遗传结构和高度遗传的情况下， 异质性特别是，通过研究一个大的PUV患者队列中的CNV，我们发现了不同的新的CNV， PUV和下尿路畸形的候选基因。我们接下来证明了小鼠转录本 剂量的这些候选基因之一，Tbx 6，导致高度渗透性发育不良和缺乏 类似于人类PUV的尿道疏通。同时，我们已经确定了一组基因， 在缺乏Sall 1的小鼠突变体中失调，Sall 1是一种转录因子，当在人类中突变时， Townes-Brocks综合征（TBS），一种以不同畸形为特征的临床实体，包括肛门直肠畸形 缺陷、PUV和尿道下裂。我们现在建议将我们的测序工作扩展到另外200个PUV三人组， 并在一个大的患者队列中复制发现以识别新基因。我们还将描述低 Sall 1和Tbx 6的泌尿道缺陷，并生成整个转录组数据集，以确定下游 靶向并促进人类的基因鉴定。本研究旨在解决 PUV，以改善对受这种严重疾病影响的儿童的诊断和个性化护理，并确定 这些途径可以适用于治疗干预。