Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessivekidney disease characterized by polyhydramnios, premature delivery,hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous,having been linked recently to mutations in an ATP- sensitive, renal outermedullary K+channel, ROMK, and earlier to mutations in the Na-K-2Clco-transporter, NKCC2. We characterized four of the mutations reported inthree heterozygous ROMK variants of antenatal Bartter's and found that eachexpressed a distinct phenotype in Sf9 cells. One mutation expressed normalfunction and appears to be an allelic polymorphism. The other threemutations produced channels with significantly reduced K+fluxes. However,the mechanisms in each case were different and reflected abnormalities inphosphorylation, proteolytic processing or protein trafficking. Thedifferent mechanisms may be important in the design of appropriate therapyfor patients with this disease.