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

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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.