U. LEEDS (UK)—The discovery of the mechanisms of a protein known to play an active part in an extremely rare inherited kidney disorder called Dent’s disease may provide a new focus for future therapies.
Caused by a genetic mutation of the X chromosome, the main symptoms of Dent’s disease are kidney stones, often followed by deterioration of kidney function, and in many cases chronic kidney failure.
The disease affects mostly men. Treatment is focused on alleviating symptoms and can involve kidney transplant. There is no cure.
“This is a rare genetic disease so it’s impossible to know the exact number of sufferers worldwide,” says Jonathan Lippiat, of the faculty of biological sciences at University of Leeds.
“Dent’s disease could be the underlying cause of kidney stones or kidney failure for a larger number of people and it could be that a number of Dent’s sufferers go undiagnosed.
“The faulty gene itself has been known about for quite a while, but there’s been no concrete evidence about the function it fulfils. That’s why we’re excited by these findings—they provide us with a whole new area to examine in the search for therapies for Dent’s disease.”
Details appear in the Journal of Physiology.
The new research uncovered the role of CLC-5, a transporter protein known to be faulty in many sufferers of Dent’s disease.
CLC-5 facilitates a crucial function by allowing certain ions to pass through cell membranes so they can reach the places they are needed.
The kidneys filter blood, removing waste, but minerals and hormones that the body needs to remain healthy need to be reabsorbed. In order for the cells in the kidney to reabsorb effectively, a process called endocytosis takes place to allow larger molecules to travel through the cell membrane.
In endocytosis, a compartment is created in the cell membrane for the molecule to enter. This compartment—endosome—needs to be acidic in order for the process to work effectively.
The research findings show that CLC-5 delivers protons into endosomes, which causes acidification to occur, so when CLC-5 is faulty, endocytosis cannot take place effectively.
“If endocytosis can’t take place we lose vital vitamins and hormones,” Lippiat explains.
“CLC-5 is actually part of a family of proteins, some of which are implicated in other diseases, so these findings could have important consequences when we’re looking at the role of other proteins in the same family.”
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