Cystinosin regulates Na(+)/H(+) exchanger 3 trafficking and function in kidney proximal tubular cells.

Cystinosis is a rare inherited disease caused by changes in the CTNS gene. This gene normally produces a protein called cystinosin, which helps move a substance called cystine out of a part of the cell known as the lysosome. When cystinosin does not work properly, cystine builds up in cells throughout the body and causes damage. Although cystinosin is found in all organs, the first major problem in cystinosis usually occurs in the kidneys. Children develop a condition called Fanconi syndrome, in which the kidney’s proximal tubule cells are unable to properly reabsorb important nutrients and minerals. Current treatment with cysteamine lowers cystine levels but does not correct Fanconi syndrome. In this study, we discovered a previously unknown role for cystinosin. Beyond transporting cystine, cystinosin helps regulate the location and function of a key sodium transporter called NHE3 in kidney proximal tubule cells. NHE3 is essential for sodium and fluid reabsorption. Without functional cystinosin, NHE3 is misplaced inside the cell and cannot work properly, leading to impaired sodium uptake. We confirmed this abnormal NHE3 localization in kidney tissue from cystinosis patients and in a mouse model of the disease. Restoring the normal CTNS gene in affected kidney cells corrected the NHE3 defect. In mice, transplantation of healthy blood-forming stem cells restored NHE3 expression at the correct location in kidney cells and improved features of Fanconi syndrome. These findings show that cystinosin has an additional, evolutionarily conserved role in guiding sodium transporter trafficking in kidney cells. This new understanding of disease mechanisms helps explain why Fanconi syndrome occurs in cystinosis and may open the door to new treatment strategies beyond cystine depletion alone.