Human hypertension caused by mutations in WNK kinases

  • Science. 2001 Aug 10;293(5532):1107-12. doi: 10.1126/science.1062844.
F H Wilson  1 ,  S Disse-Nicodème ,  K A Choate ,  K Ishikawa ,  C Nelson-Williams ,  I Desitter ,  M Gunel ,  D V Milford ,  G W Lipkin ,  J M Achard ,  M P Feely ,  B Dussol ,  Y Berland ,  R J Unwin ,  H Mayan ,  D B Simon ,  Z Farfel ,  X Jeunemaitre ,  R P Lifton
Affiliations
  • 1. Howard Hughes Medical Institute; Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06510 USA.
PMID: 11498583 DOI: 10.1126/science.1062844
Abstract

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring Hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine Kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK Kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.