Human Hypertension Caused by Mutations in WNK Kinases

TLDR

Hypertension is a major public health problem of largely unknown cause, and the implicated genes encode WNK family kinases that localize to the distal nephron—WNK1 is cytoplasmic while WNK4 resides at tight junctions. The study identifies two genes causing pseudohypoaldosteronism type II—a Mendelian hypertension syndrome—and proposes that WNK kinases and their signaling pathways could be novel targets for antihypertensive therapy. We discovered that WNK1 mutations are large intronic deletions elevating expression, while WNK4 mutations are missense clustered in a conserved segment, both leading to pseudohypoaldosteronism type II with hypertension.

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.