Genetics of Congenital Obstructive Uropathy

描述(申请人提供)：先天性肾脏和尿路畸形(CAKUT)占全球儿童终末期肾功能衰竭的40%-50%。在CAKUT分类中，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发现的最常见的尿路异常，发生在高达2%的正常妊娠中。先天性梗阻性尿路病可表现为家族性或散发性疾病，表型表达高度可变。由于缺乏对原发发病机制的基本认识，诊断和治疗选择严重受限。我们最近在斑马鱼中实施了完整的外显子组测序并进行了功能建模，以确定高达2.3%的先天性梗阻性尿路疾病和相关尿路畸形患者的DSTYK显性突变(Sanna-Cherchi等人，New Engl J Med 2013)。在肾脏形成过程中，DSTYK编码的蛋白作为成纤维细胞生长因子信号的正向调节因子。这项研究展示了在动物模型中将整个外显子组测序与功能建模相结合来识别新的致病突变的能力，这些突变的特征是高度遗传异质性、不完全外显、表型表达可变和小/中等家系大小。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在胚胎发育和肾脏发生过程中的功能，将我们的基因鉴定工作扩展到另外50个常染色体显性遗传性先天性梗阻性尿病家族，并在斑马鱼中进行功能建模以确定新的易感基因。这项研究将有助于了解先天性梗阻性尿路疾病在人类和动物模型中的发病机制，并将有助于开发新的诊断和治疗策略。

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.