Discovery and functional characterization of novel single-gene causes and genetic modifiers in nephronophthisis

慢性肾脏疾病（CKD）影响着全球10-15%的人口，并且越来越被认为是一个重大的全球健康负担。遗传性肾病是CKD和终末期肾病（ESRD）的第五大常见原因。虽然成人常染色体显性遗传性多囊肾病（ADPKD）是主要疾病，但肾单位营养不良（NPH）是生命最初几十年中最常见的遗传原因。NPH是一种慢性肾小管间质性肾病，其特征是间质纤维化和微囊肿形成，具有隐性遗传模式。NPH可以表现为孤立的肾脏疾病或伴有肾外器官受累的综合征疾病。与ADPKD一起，NPH属于肾脏纤毛病谱，在初级纤毛依赖性信号传导途径中共享潜在缺陷。虽然超过20个NPH致病基因的鉴定已经推进了我们的理解，但大多数临床疑似NPH病例仍然没有解决。拟议的项目旨在i）使用基于靶向基因组、全外显子组和全基因组测序的逐步策略鉴定新型NPH疾病基因，ii）检测综合征和非综合征NPH 1患者队列中家族间疾病变异性的遗传修饰剂，iii）表征细胞和动物NPH模型中关于纤毛功能的新型疾病机制，以测试新型药物方法。Sophie Saunier在巴黎Imagine遗传病研究所的工作组提供了一个优秀的基础设施，其特点是在纤毛病领域的创新研究方法和丰富的研究经验，以成功地开展拟议的项目。

Chronic kidney disease (CKD) affects as many as 10-15% of the worldwide population and is increasingly recognized as a significant global health burden. Inherited kidney diseases represent the fifth most common cause of CKD and end-stage renal disease (ESRD). While among adults autosomal-dominant polycystic kidney disease (ADPKD) is the prevailing condition, nephronophthisis (NPH) constitutes the most frequent genetic cause in the first decades of life. NPH is a chronic tubulointerstitial nephropathy characterized by interstitial fibrosis and microcyst formation with a recessive mode of inheritance. NPH can either present as isolated renal disease or as syndromic disease with extra-renal organ involvement. Together with ADPKD, NPH belongs to the spectrum of renal ciliopathies sharing underlying defects in primary cilia-dependent signaling pathways. Although identification of more than 20 NPH causing genes has advanced our understanding, the majority of clinically suspected NPH cases still remain genetically unsolved. The proposed project aims to i) identify novel NPH disease genes using a step-wise strategy based on targeted-gene panel, whole exome, and whole genome sequencing, ii) detect genetic modifiers accounting for interfamilial disease variability in a cohort of syndromic and non-syndromic NPHP1-patients, iii) characterize novel disease mechanisms with regards to ciliary function in cellular and animal NPH-models to test novel pharmaceutical approaches. The work group of Sophie Saunier at the Imagine Institute of Genetic diseases in Paris provides an excellent infrastructure characterized by innovative research methods and profound research experience in the field of ciliopathies to successfully pursue the proposed project.