Saunier's lab

Our research aims at unraveling the pathogenesis of nephronophthisis (NPH) and renal hypodysplasia (RHD), two major genetic causes of renal insufficiency in children. Nephronophthisis (NPH) is an autosomal recessive nephropathy, characterized by interstitial fibrosis and formation of tubular cysts, which represents the most common genetic cause of end-stage renal disease in children. NPH can be isolated or associated with extra-renal anomalies including retinal dystrophy, cerebellar vermis hypoplasia, skeletal dysmorphisms and/or situs inversus. The specific association of these anomalies defines complex syndromes now called “ciliopathies”. Renal hypodysplasia (RHD) is a phenotypically heterogeneous disorder that encompasses a spectrum of kidney development defects including renal agenesis, hypoplasia (defect in the number of nephrons) and dysplasia with or without cysts. It is also one of the most frequent cause of end-stage renal disease in children and the most severe forms (bilateral renal agenesis and multicystic dysplasia) are diagnosed in utero and justify medical termination of pregnancy. During the past 15 years, our group has participated in the identification of mutations in 10 out of the 18 genes that cause NPH (either isolated or syndromic forms), and the demonstration that most of the proteins encoded by these genes, nephrocystins (NPHP) and intraflagellar transport components (IFTA and IFTB), are localized at the primary cilium. This ubiquitous and conserved microtubule-based structure is found at the apical membrane of kidney epithelial cells where it functions as a flow mechano/chemo-sensor to mediate signals that regulate morphogenesis of kidney tubules and tissue homeostasis, thus preventing cysts formation. Our recent work based on the use of in vitro kidney epithelial cell models, patient fibroblasts and in vivo models including mouse and zebrafish, demonstrated that the NPHP and IFT proteins are critical for ciliary function, cell polarity and epithelial morphogenesis.