Altered Cell Biology of ClC‐5 by Dent's Disease Causing Mutations

Dent's disease is a genetic disorder characterised by proteinuria, nephrocalcinosis and kidney failure. This disorder is caused by mutations of the CLCN5 gene which encodes the ClC‐5 voltage‐gated chloride channel. ClC‐5 is found primarily in the proximal tubule of the kidney where it is known to play a vital role in the reabsorption of small proteins from the glomerular filtrate, although the precise role that it plays in this process remains controversial. Using a multidisciplinary approach involving patch‐clamp electrophysiology, protein chemistry and imaging techniques, we have investigated the functional and cell biological consequences of several published Dent's disease mutations. The mutations display a wide variety of effects, ranging from total loss‐of‐function due to intracellular retention through to no discernible effect on electrophysiological properties, cell surface targeting, subcellular distribution or associated cellular processes (endosomal acidification and protein uptake). Further characterisation of the functional and cell biological consequences of Dent's disease mutations may be useful as tools to clarify the role played by ClC‐5 in mediating endosomal acidification and protein re‐uptake from the proximal tubule of the kidney.