Progress in the study of a rare genetic syndrome with renal and cardiac alterations

After the identification of the gene responsible for the syndrome, the mechanism underlying its onset was also described, opening the way to the study of new possible therapeutic strategies.
Oct 05, 2023
Progress in the study of a rare genetic syndrome with renal and cardiac alterations
An increased in-depth knowledge of the mechanisms underlying a rare disease characterized by renal damage associated with cardiomyopathy has been made possible thanks to an intense collaboration between two research centers in Campania, the Telethon Institute of Genetics and Medicine (TIGEM) and the Biogem of Ariano Irpino. This knowledge could open the way to the development of new therapeutic strategies against the disease, a very rare pathology that affects only 10 families in the world. The main authors of this study are Professor Andrea Ballabio, director of TIGEM, with researchers Irene Sambri and Marco Ferniani, and Professor Francesco Trepiccione, director of Biogem's Translational Nephrology Laboratory.

''It all began - explains Professor Trepiccione - when a family came to our attention in which many members presented a renal clinical picture marked by the loss, in the urine, of large quantities of potassium and magnesium, with greatly lower levels of these ions in the blood- This expose them to cramps, tiredness and, above all, to the risk of sudden cardiac death''. ''This picture - Trepiccione continues - is common to many other renal tubulopathies, i.e. diseases characterized by particular alterations in renal function, but in this family it was associated with cardiac alterations present already at a young age and very severe, to the point of requiring a heart transplant''.

The first step was the identification, in the members of one of the families, of a particular mutation in a gene called RRAGD of which other mutations associated with renal tubulopathy with dilated cardiomyopathy were already described. «Previous studies conducted in my laboratory - explains Professor Ballabio - had already demonstrated that the protein encoded by this gene (RagD) represents an important regulator of other fundamental molecules for the cell: mTORC1, a protein complex capable of "sensing" the environmental conditions of the cell, and TFEB, involved in the control of cellular waste disposal, in turn regulated by mTORC1".

“Thanks to these new experiments conducted at Tigem we have understood – Sambri and Ferniani specify – that the RagD mutations responsible for the disease make this protein always 'active'', which in turn involves an alteration of the activity of mTORC1 and TFEB , significantly influencing various cellular functions necessary for the normal functioning of renal and cardiac tissue”. In particular, cells respond poorly to various environmental stimuli, triggering a cascade of changes that contribute to the onset of renal tubulopathy and cardiomyopathy. Now the working hypothesis is that restoring TFEB function could represent an effective therapeutic strategy for this disease and for other forms of renal tubulopathy and cardiomyopathy not associated with RagD mutations, but which could depend on mutations of other genes involved in the regulation of mTORC1 and TFEB. “In the meantime – Trepiccione informs – an international collaboration has been estabilished with other centers that follow patients suffering from this condition, in order to define effective therapies in a short time”.

The study is the result of important national and international collaborations with the groups of Giancarlo Parenti of the Federico II University, Vincenzo Nigro of the University of Campania “Luigi Vanvitelli” and Leopoldo Staiano of the Institute of Genetic and Biomedical Research-IRGB (CNR) of Milan (all of them are also Tigem researchers), Milena Bellin of the University of Leiden and Padova, Lukas Huber of the University of Innsbruck and Carlo De Virgilio of the University of Fribourg. The results were published in Nature Communication journal, which included it among the best works published in the year for the area of ​​clinical and translational research. “A demonstration of how important it is for the entire scientific community” concludes Ballabio.

More about Ballabio's group: