CLCN5

The CLCN5 gene provides instructions for making a protein called ClC-5 that transports charged atoms (ions) across cell membranes. Specifically, ClC-5 exchanges negatively charged atoms of chlorine (chloride ions) for positively charged atoms of hydrogen (protons or hydrogen ions). Based on this function, ClC-5 is known as a H⁺/Cl^- exchanger.

ClC-5 is found primarily in the kidneys, particularly in structures called proximal tubules. These structures help to reabsorb nutrients, water, and other materials that have been filtered from the bloodstream. The kidneys reabsorb needed materials into the blood and excrete everything else into the urine.

Within proximal tubule cells, ClC-5 is embedded in specialized compartments called endosomes. Endosomes are formed at the cell surface to carry proteins and other molecules to their destinations within the cell. ClC-5 transports hydrogen ions into endosomes and chloride ions out, which helps these compartments maintain the proper acidity level (pH). Endosomal pH levels must be tightly regulated for proximal tubule cells to function properly.

Dent disease - caused by mutations in the CLCN5 gene

About 150 mutations in the CLCN5 gene have been found to cause Dent disease 1, a chronic kidney disorder that can cause kidney failure. Most of the mutations lead to the production of an abnormally short, nonfunctional version of ClC-5 or prevent cells from producing any of this protein. A loss of ClC-5 alters the regulation of endosomal pH, which disrupts the overall function of proximal tubule cells and prevents them from reabsorbing proteins and other materials into the bloodstream. As a result, proteins are lost through the urine (tubular proteinuria). A failure to reabsorb calcium and other nutrients into the bloodstream can cause bone defects, kidney stones, and related health problems in people with Dent disease 1. Abnormal proximal tubule function ultimately leads to kidney failure in most affected individuals.

Genetics Home Reference provides information about hereditary hypophosphatemic rickets, which is also associated with changes in the CLCN5 gene.