Research Article

Human Hypertension Caused by Mutations in WNK Kinases

Science  10 Aug 2001:
Vol. 293, Issue 5532, pp. 1107-1112
DOI: 10.1126/science.1062844

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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.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: richard.lifton{at}yale.edu

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