Sophie SAUNIER

Hereditary kidney diseases account for around 25 per cent of cases of end-stage renal failure in children and 15 per cent in adults, and the only replacement therapies available are dialysis and/or kidney transplantation. Our laboratory's research projects focus on four major kidney diseases that affect different regions of the nephron – the functional unit of the kidney – and stem from our pioneering work on the identification of three key genes: CTNS (in 1998), NPHS2 and NPHP1 (in 2000), which are involved in cystinosis, corticosteroid-resistant nephrotic syndrome (CRNS) and nephronophthisis (NPH), respectively.

We have thus developed two major lines of research dedicated to exploring the genetic basis and pathophysiology of these four diseases: one focusing on the study of renal ciliopathies (in particular nephronophthisis) and congenital abnormalities of the urinary tract (in particular renal hypodysplasia) in S. Saunier's group, and the other on the study of isolated or syndromic corticosteroid-resistant nephrotic syndrome (Galloway-Mowat syndrome) and cystinosis in C. Antignac's group.

Together, our main objectives are as follows:

• To identify new candidate genes or modifier genes involved in these conditions, using innovative whole-exome sequencing (WES) approaches or approaches targeting candidate genes (> 1,600 genes), whole-genome sequencing (WGS) or transcriptome analysis (RNA-Seq) using large patient cohorts, which are continually expanded through collaboration with the clinical departments at Necker-Enfants Malades Hospital
• To identify mutations that have hitherto been difficult to detect in new genes or in genes already implicated in kidney diseases. These mutations may correspond to intronic variants or deletions, or to variants that do not alter the coding region but lead to alternative splicing; these are and will be identified through combined genome and transcriptome studies of patient-derived cells.
• To understand the molecular and cellular mechanisms leading to patients' phenotypes. To this end, we carry out functional studies on in vivo models (mice and zebrafish) and/or in vitro cellular models such as renal epithelial cell lines (podocytes, tubular cells) and renal cells isolated from patients' urine, or, more recently, renal organoids differentiated from induced pluripotent stem cells (iPSCs). We use CRISPR/Cas9 technology to knock out genes of interest or to introduce mutations into renal cells, iPSCs, zebrafish and/or mice.
• To identify new therapeutic targets, the molecules of which are currently being studied in our laboratory for nephronophthisis or hereditary podocytopathies associated with certain mutations in podocin.

• Nephronophthisis

Nephronophthisis is an autosomal recessive nephropathy (NPH), characterised by interstitial fibrosis and the formation of tubular cysts. It is the most common genetic cause of end-stage renal failure in children. NPH may occur in isolation or in association with extra-renal abnormalities. The specific combination of these abnormalities defines complex syndromes known as ‘ciliopathies'. Drawing on large patient cohorts (>1,000 NPH families) collected by a multicentre clinical network and through the development of innovative approaches based on NGS, our group has identified 13 of the 22 genes involved in NPH (NPHP). The vast majority of NPHP genes encode proteins that play a key role in the primary cilium, a sensory organelle present on the surface of many cell types, including renal tubular cells. NPH is therefore a renal ciliopathy and may be associated with involvement of other organs (retina, cerebellum, skeleton) in so-called syndromic forms.

• CAKUT and Renal Hypodysplasia

Renal hypodysplasia (RH) is a phenotypically heterogeneous disorder encompassing a broad spectrum of renal developmental defects, including renal agenesis, hypoplasia and dysplasia with or without cysts, and falls within the CAKUT (Congenital Anomalies of the Kidney and Urinary Tract). It is also one of the most common causes of end-stage renal failure in children. Our group has identified five genes amongst the forty or so genes involved in their development and is contributing to the understanding of the molecular and cellular mechanisms leading to the development of these phenotypes. We have also identified phenotypic and genotypic overlaps between CAKUT and renal ciliopathies (NPHP9/NEK8). Nephrotic syndrome is characterised by massive proteinuria, hypoalbuminaemia, hyperlipidaemia and oedema. The identification of genes involved in rare familial forms of corticosteroid-resistant nephrotic syndrome (CRNS) has highlighted the crucial role of the podocyte – a highly specialised glomerular cell – in maintaining the integrity of the glomerular filtration barrier. Nearly 60 genes, mutations in which are implicated in the development of the disease, have been identified in patients. There is considerable genetic heterogeneity, and in around half of familial cases of CRNS, the genes responsible for the disease remain unknown; the molecular aetiology of these cases is being actively investigated through high-throughput sequencing projects aimed at identifying new genes or deep intronic mutations.

Kidney disease may occur in isolation or be associated with several extra-renal manifestations, the most common of which are neurological, as in Galloway-Mowat syndrome (GAMOS), characterised by the combination of SNCR, microcephaly and neurological disorders, the genetic basis of which has been identified by our group (WDR73; genes of the KEOPS complex).

Our group is contributing to the understanding of the cellular mechanisms involved in the development of GAMOS, in particular by studying the role of RNA modifications in the pathophysiology of the disease.