Human hypertension caused by mutations in WNK kinases

Hypertension is a major public health problem of largely unknown cause. Her e, we identify two genes causing pseudohypoaldosteronism type II, a Mendeli an trait featuring hypertension, increased renal salt reabsorption, and imp aired K+ and H+ excretion. Both genes encode members of the WNK family of s erine-threonine kinases. Disease-causing mutations in WNK1 are large intron ic deletions that increase WNK1 expression. The mutations in WNK4 are misse nse, which cluster in a short, highly conserved segment of the encoded prot ein. Both proteins localize to the distal nephron, a kidney segment involve d in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 locali zes to tight junctions. The WNK kinases and their associated signaling path way(s) may offer new targets for the development of anti hypertensive drugs .