The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the gene (solute carrier family 12 member 3) located in 16q13. A loss of NCC function causes Gitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Over a hundred different mutations in the NCC gene have been identified. Molecular biology The sodium-chloride symporter or NCC is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporter, along with the potassium-chloride cotransporters (K+-Cl− cotransporters or KCCs), the sodium-potassium-chloride cotransporters (Na+-K+-Cl− cotransporters or NKCCs) and orphan member CIP (cotransporter interacting protein) and CCC9. The sodium-chloride symporter's protein sequence has a high degree of identity between different mammalian species (over 90% between human, rat and mouse). The gene encodes for a protein of 1,002 to 1,030 amino acid residues. NCC is a transmembrane protein, presumed to have a hydrophobic core of either 10 or 12 transmembrane domains with intracellular amino- and carboxyl-terminus domains. The exact structure of the NCC protein is unknown, as it has not yet been crystallized. The NCC protein forms homodimers at the plasma membrane. N-glycosylation occurs in two sites in a long extracellular loop connecting two transmembrane domains within the hydrophobic core. This posttranslational modification is necessary for proper folding and transport of the protein to the plasma membrane. Function Because NCC is located at the apical membrane of the distal convoluted tubule of the nephron, it faces the lumen of the tubule and is in contact with the tubular fluid. Using the sodium gradient across the apical membrane of the cells in distal convoluted tubule, the sodium-chloride symporter transports Na+ and Cl− from the tubular fluid into these cells. Afterward, the Na+ is pumped out of the cell and into the bloodstream by the Na+-K+ ATPase located at the basal membrane and the Cl− leaves the cells through the basolateral chloride channel ClC-Kb. The sodium-chloride symporter accounts for the absorption of 5% of the salt filtered at the glomerulus. NCC activity is known to have