Note that the phenotypes of both WNK4 and SPAK knockout mice closely resemble the human disorder Gitelman syndrome, caused by inactivating mutations in SLC12A3 encoding NCC, and recapitulated in mouse models carrying Gitelman syndrome mutations.15,36 In each case, there is loss of NCC activity accompanied by hypokalemia and metabolic alkalosis. This evidence concerns the gene WNK4 and Gitelman syndrome.