Genetics of Congenital Obstructive Uropathy

先天性梗阻性尿病的遗传学

• 批准号: 9324211
• 负责人: Simone Sanna-Cherchi
• 金额: $ 51.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324211
• 关键词: Animal Model; Biological Assay; Candidate Disease Gene; Categories; Cell Culture Techniques; Childhood; Code; Communities; Computer Simulation; DNA Resequencing; Data; Development; Diagnostic; Disease; Embryonic Development; Family; Fibroblast Growth Factor; Genes; Genetic; Genetic Crosses; Genetic Heterogeneity; Genetic Screening; Genetic study; Goals; Human; Hydronephrosis; Kidney; Kidney Failure; Knock-out; Knockout Mice; Modeling; Molecular Profiling; Mus; Mutation; Pathogenesis; Pathogenicity; Patients; Penetrance; Phenotype; Pregnancy; Proteins; Research; Signal Transduction; Susceptibility Gene; Testing; Therapeutic; Transgenic Organisms; Ultrasonography; Urinary tract; Variant; Zebrafish; base; cohort; congenital anomaly; cost; data sharing; disease-causing mutation; exome; exome sequencing; genetic pedigree; imaging study; innovation; insight; malformation; mouse model; nephrogenesis; next generation sequencing; novel; novel diagnostics; novel therapeutic intervention; overexpression; prenatal; public health relevance; trait; urinary tract obstruction

DESCRIPTION (provided by applicant): Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for 40-50% of pediatric end-stage kidney failure worldwide. Among CAKUT categories, congenital obstructive uropathy represents a common and severe form of malformation. Congenital hydronephrosis is the most frequent anomaly of the urinary tract detected by prenatal ultrasound, occurring in up to 2% of normal pregnancies. Congenital obstructive uropathy can occur as familial or sporadic disease with highly variable phenotypic expression. Due to paucity of fundamental insight about primary pathogenesis, diagnostic and therapeutic options are severely limited. We recently implemented whole exome sequencing combined to functional modeling in zebrafish to identify dominant mutations in DSTYK in up to 2.3% of patients with congenital obstructive uropathy and associated urinary tract malformations (Sanna-Cherchi et al, New Engl J Med 2013). The protein encoded by DSTYK acts as a positive regulator of fibroblast growth factor (FGF) signaling during nephrogenesis. This study illustrates the power of combining whole exome sequencing with functional modeling in animal models to identify novel disease causing mutations in traits characterized by high genetic heterogeneity, incomplete penetrance, variable phenotypic expression, and small/medium pedigree size. Here we propose to characterize the function of DSTYK during embryonic development and nephrogenesis in cell cultures and in mouse models harboring Dstyk mutations, to extend our gene identification effort to 50 additional families with autosomal dominant congenital obstructive uropathy and to perform functional modeling in zebrafish to identify novel susceptibility genes. This study will provide insight into the pathogenesis of congenital obstructive uropathy in humans and animal models and will help develop new diagnostic and therapeutic strategies.

描述（由申请人提供）：先天性肾脏和尿路异常（先天性肾脏和尿路异常）占全球儿童终末期肾衰竭的40-50%。在ckut类别中，先天性梗阻性尿路病变是一种常见且严重的畸形。先天性肾积水是产前超声检测到的最常见的尿路异常，在正常妊娠中发生率高达2%。先天性梗阻性尿路病变可以发生为家族性或散发性疾病，具有高度可变的表型表达。由于缺乏对主要发病机制的基本认识，诊断和治疗选择受到严重限制。我们最近在斑马鱼中实施了全外显子组测序结合功能建模，以确定高达2.3%的先天性阻塞性尿路病和相关尿路畸形患者的DSTYK显性突变（sana - cherchi等，New Engl J Med 2013）。DSTYK编码的蛋白在肾形成过程中作为成纤维细胞生长因子（FGF）信号的正调节因子。该研究表明，将全外显子组测序与动物模型的功能建模相结合，可以识别具有高遗传异质性、不完全外显子、可变表型表达和中小型家系大小的特征的新型疾病突变。在这里，我们建议在细胞培养和携带DSTYK突变的小鼠模型中表征DSTYK在胚胎发育和肾形成过程中的功能，将我们的基因鉴定工作扩展到50个常染色体显性先天性梗阻性尿病家族，并在斑马鱼中进行功能建模以鉴定新的易感基因。本研究将为人类和动物模型中先天性梗阻性尿路病变的发病机制提供深入的见解，并将有助于开发新的诊断和治疗策略。