The renal tubules are responsible for the reabsorption of water and sodium from the filtrate produced by the glomerulus, the regulation of acid–base balance, maintenance electrolytes homoeostasis and blood pressure, and the excretion of organic anions and drugs. To accomplish these functions, a large number of specific transport proteins and channels are precisely localized in the tubular cell membranes (apical and basolateral). Consequently, mutations in the genes encoding these proteins cause a wide range of tubulopathies. These rare diseases may share clinical and biochemical characteristics, therefore, in order confirm the clinical diagnosis it is necessary to detect a pathogenic mutation in the gene implicated.

We are interested in the genetic basis of several renal hereditary diseases, particularly primary tubulopathies that affect the function of the proximal tubule and the loop of Henle. These include Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, renal hypouricemia, Bartter syndrome and Lowe syndrome. We have identified mutations in many families with these disorders, and in collaboration with several Spanish groups have created and consolidated RenalTube, a web-page approach that offers medical professionals the possibility of participating in the development of a clinical and genetic database of patients with different primary tubulopathies. RenalTube improves the recruitment of data, promotes the understanding of underlying mechanisms of renal tubulopathies, provides more accurate diagnostic and follow-up criteria, and will improve the overall care of the patients. Currently, RenalTube is offering the analysis of 26 genes associated with 23 disorders.

Our investigations are also aimed at determining the functional consequences of presumed missense and silent mutations in pre-mRNA splicing. For this purpose, we use bioinformatics tools and a minigene system. We have shown that exonic mutations in several genes (CLDN16, CLDN19, CLCN5, OCRL, PKD1 and PKD2) associated with renal disease can alter the splicing of the respective pre-mRNAs by different mechanisms, causing drastic defects in the protein. In collaboration with Dr. David Machado (University of La Laguna), we are using immunocytochemical techniques to study the consequences of specific CLCN5 disease-causing mutations (Dent-1), located in α-helices of CLC-5, on the subcellular localization of the mutant proteins. Finally, we have generated and characterized a knock-in Clcn5 mouse that we are using as a model to investigate potential therapeutic strategies for Dent-1 disease.

Ongoing projects and financial support

Pre-clinical trial of VX-809 (lumacaftor) for the treatment of Dent disease-1 in a knock-in mouse model<
Grant Oliver Wrong Research Program Award from the Dent Disease Foundation (EE. UU.) (2022-2023).

Investigación de estrategias terapéuticas para la enfermedad de Dent-1 y adaptación de RenalTube a las necesidades de los pacientes con tubulopatías primarias
Grant PI20/00652 from Instituto de Salud Carlos III, co-financed by European Regional Development Fund. (2021-2023)

Characterization of CLCN5 gene mutations that cause Dent disease and generation of a knock-in mouse
Grant D18-003 from Asdent – Asociación de la enfermedad de Dent (2015-2022)