ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3

The mutations in the CLCNKBgene encoding the ClC-Kb chloride channelare responsible for Bartter syndrometype 3, one of the four variants of Bartter syndromein the genetically based nomenclature. All forms of Bartter syndromeare characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism, but Bartter syndrometype 3 has the most heterogeneous presentation, extending from severe to very mild. A relatively large number of CLCNKBmutations have been reported, including gene deletions and nonsenseor missense mutations. However, only 20 CLCNKBmutations have been functionally analyzed, due to technical difficulties regarding ClC-Kb functional expression in heterologous systems. This review provides an overview of recent progress in the functional consequences of CLCNKBmutations on ClC-Kb chloride channelactivity. It has been observed that 1) all ClC-Kb mutants have an impaired expression at the membrane; and 2) a minority of the mutants combines reduced membrane expression with a...