Genetics and cell biology
Molecular genetics of renal disorders
Chronic kidney disease (CKD) impacts over 10% of the global population, leading to significant morbidity and mortality. Around 25% of CKD patients have a family history of the disease, with Mendelian genetic factors estimated to be responsible for about 10% of adult end-stage renal disease cases. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is the third most common monogenic cause of CKD. ADTKD can be caused by mutations in different genes, including UMOD, encoding uromodulin, and REN, encoding renin.
Research activity
The main research focus of the group is to gain insight into the biology of uromodulin, its role in renal function and in chronic diseases of the kidney. Uromodulin is the most abundant protein in normal urine, specifically produced in the kidney by epithelial cells of the kidney nephron. It plays a role in the protection against urinary tract infections (UTI) and renal stones, in renal salt handling and innate immunity. The UMOD gene represents a paradigm of continuous genetic risk of disease, from rare mutations causing Mendelian disease to intermediate-effect size variants to common alleles associated with risk of CKD and hypertension. Through human, cellular and animal studies, we demonstrated the biological effect of common variants, ie increase gene expression, and their causal link with salt- sensitive hypertension and to age-dependent renal damage. The group also showed that UMOD risk alleles have been likely kept at high frequency through evolution due to their protective effect against UTI.
The group demonstrated that UMOD mutations associated with ADTKD-UMOD lead to ER retention of mutant protein, ER stress and Unfolded Protein Response (UPR) activation, and early induction of inflammation. We are currently investigating the mocular pathogenesis and testing potential therapetic strategies in specific in vivo and in vitro models of the disease.
More recently, we expanded our interest to other inherited kidney diseases due to defective protein trafficking. The localisation of ADTKD-related REN mutations correlate with disease severity. We indeed demonstrated that mutations in mature renin lead to mutant protein retention in the ER and cause a mild, late-onset disease. In contrast, mutations in the pre- or pro-sequence result in a more severe, early-onset disease and we showed that they lead to mistargeting of renin to mitochondria, leading to mitochondrial fragmentation and impaired import. In the context of Fabry disease, a lysosomal disorder due to mutations in the GLA gene encoding α-galactosidase A, we demonstrated that missense mutations can be ER retained and induce UPR, depending on their structural impact. This suggests an unprecedented mechanism of disease, associated with gain of function effect of GLA mutations.
