Dent's disease is a rare genetic disorder that affects the kidney and can progress to kidney failure before age 50. This pathology is produced by mutations in the CLCN5 gene, which codes for the ClC-5 protein. This protein has an especially relevant role in the normal functioning of the kidney, specifically for the reabsorption of filtered proteins from the blood, that is, to prevent them from being lost through the urine. There are multiple types of mutations that prevent this process from being carried out correctly. Currently there are no markers for the evolution of the disease, no curative treatment or ongoing clinical trials. A project, led by Dr. Anna Meseguer and Dr. Eduard Sarró from the CIBBIM-Nanomedicine-Renal Physiopathology research group, has developed models of human kidney cells that allow an in-depth study of the pathophysiological mechanisms of Dent's disease and that, in the future, they will serve as a platform to test the efficacy of new drugs."From this study, we have seen from this study that, in Dent's disease, kidney cells lose their epithelial phenotype, that is, their identity as kidney cells, and therefore do not function properly", says Dr. Eduard Sarró.The team has confirmed that the process of endocytosis or reabsorption of proteins through vesicles is affected in cells that express mutated forms of this protein, which validates the cellular models. In addition, they have seen that other parameters related to pathology, such as proliferation and differentiation of cells, are altered. "We have also analyzed the expression pattern of different proteins that are altered in the disease, which can help to design drugs that are aimed at the affectations that patients have", highlights Dr. Anna Meseguer, head of the research group CIBBIM-Nanomedicine-Renal Pathophysiology.One of the affectations seen in Dent's disease is Fanconi syndrome, a disorder of the cells of the renal tubule. This syndrome, however, is not exclusive to this disease, but can also be caused, for example, by taking certain drugs, multiple myeloma, diabetes ... "To study the mechanisms that produce Fanconi syndrome from a rare disease, as is Dent's disease, it could also help other much more common diseases or conditions", says Dr. Meseguer.Part of the results obtained in this project have been published in https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddab131/6275366 Human Molecular Genetics.A new cellular model to investigate Dent's diseaseThese findings have been made from the development of a cellular model to study Dent's disease. Researchers have used kidney cells where they have incorporated various types of mutations in the CLCN5 gene, each of which corresponds to more or less serious effects of the disease. Specifically, what happens when there is a specific change in an amino acid (Glu527Asp or Ile524Lys) or when an amino acid is eliminated (Val523Del) has been analyzed. Some of these mutations correspond to Vall d'Hebron patients.These cell lines allow us to know exactly the effect of each mutation, since the only difference between the different lines is the specific mutation. In fact, since they are the same cells, they have exactly the same genetic background. "The creation of these cellular models allows studying the pathophysiological mechanisms of the disease and understanding its evolution. Furthermore, in the future they will allow us to test the efficacy of drugs that are being developed", explains Dr. Mónica Duran, a researcher from the same group and first author of the article.The study was carried out in collaboration with Dr. Gema Ariceta of the Pediatric Nephrology Service of the Vall d'Hebron Hospital and with the group of Dr. Vivek Malhotra of the Center for Genomic Regulation (CRG) within the framework of the https://phd4md.crg.eu/ PhD4MD program. This program has allowed Dr. Carla Burballa (also author of the article) to develop her doctoral thesis, under the direction of Drs. Meseguer, Malhotra i Cantero. It should be noted that the project has been possible thanks to the support of https://www.asdent.es/ Asdent, a non-profit association created in 2011 with the aim of obtaining funds in favor of research in Dent's disease, and that it has allowed the development of this in a sustained manner. project over the last six years. ReferènciaMónica Durán, Carla Burballa, Gerard Cantero-Recasens, Cristian M Butnaru, Vivek Malhotra, Gema Ariceta, Eduard Sarró, Anna Meseguer, Novel Dent Disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function, Human Molecular Genetics, 2021,, ddab131, https://doi.org/10.1093/hmg/ddab131 https://doi.org/10.1093/hmg/ddab131