Molecular phenotype of mutations in epithelial chloride channels

Chlorides channels mediate the flux of chloride ion through cell membranes and they are involved in essential physiological processes such as neurotransmission, skeletal muscle tone and fluid transport between the blood and hollow organs such as kidney tubules. Mutations in chloride channels can lead to epilepsy, muscle rigidity and tubular obstruction. Mutations in the specific chloride channel called CIC-5 cause Dent's disease, an X-linked renal desease associated with loss of protein, phosphate and calcium in the urine, renal stones and in severe cases, renal failure. Recent evidence suggests that mutations in CIC-5 cause disease because of a primary defect in chloride flux through membranes of specialized compartments or organelles inside cells called endosomes. Without proper chloride channel activity, endosomes are incapable of their normal function, namely shuttling receptor proteins (proteins important in handling urinary hormones, protein and phosphate) to and from their site of action in the kidney. We have several goals in our research. We will determine how CIC-5 channels normally get to endosome membranes and once there, how they work to allow the flux of chloride ion. Further, we will examine how disease causing mutations affect targeting and channel function so that we can define the mechanism underlying disease at the molecular level and provide the derailed knowledge required for future identification of specific therapeutic tools.