Abstract
The specific causes of elevated blood pressure cannot be determined in the vast majority of patients with hypertension. However, identification of genes causing rare Mendelian forms of hypertension has provided penetrating insights into the basic mechanisms of human hypertension, highlighting the key role of altered sodium handling by the kidney as a final common pathway in hypertension pathogenesis (1). Pseudohypoaldosteronism type II (PHAII) is one of these Mendelian syndromes, characterized by the unusual combination of hypertension and high levels of potassium in the blood (hyperkalemia). The Lifton laboratory had previously found mutations in four distinct genes that can cause PHAII (2, 3). In PNAS, Shibata et al. show that impaired ubiquitination of With no lysine kinases (WNKs), key molecular switches for regulating electrolyte flux in the distal nephron, explain clinical features of PHAII (4).
Highlights
Several years ago, Lifton and colleagues identified causal mutations in the genes encoding With no lysine kinases (WNKs)-1 and -4 in Pseudohypoaldosteronism type II (PHAII) (3)
Dominant mutations in Kelch-like 3 (KLHL3) consisted of missense variants clustering in the kelch propeller domains involved in substrate binding or the brac tramtrack broad complex (BTB) domains responsible for binding to Cullin 3 (CUL3), whereas recessive mutations were scattered throughout the protein and included premature deletions and frameshifts, consistent with loss-of-function (2)
Shibata et al (4) first used a combination of immunoprecipitation and protein mass spectrometry to identify binding partners of KLHL3. These studies confirmed the association between KLHL3 and CUL3, and found that KLHL3 binds both WNK1 and WNK4, the two other proteins implicated in PHAII pathogenesis
Summary
Lifton and colleagues identified causal mutations in the genes encoding WNK-1 and -4 in PHAII (3). In PNAS, Shibata et al show that impaired ubiquitination of With no lysine kinases (WNKs), key molecular switches for regulating electrolyte flux in the distal nephron, explain clinical features of PHAII (4). This finding triggered intense study of these unique kinases, identifying roles for WNK-1 and -4 in regulation of sodium and potassium flux in the distal nephron.
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