DOI: 10.1016/S0140-6736(01)05672-0 PII: S0140-6736(01)05672-0 Copyright © 2001 Elsevier Science Ltd. All rights reserved.
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Genes raise hopes for deciphering hypertension Angela Pirisi Available online 14 August 2001.
Angela Pirisi
An international team of researchers has identified two enzyme-encoding gene mutations (hWNK1 and hWNK4) that underlie a rare form of hypertension called pseudohypoaldosteronism type II (PHAII), and may help to shed light on more common forms of the condition.
This finding implicates the WNK kinases, or other components of this signalling pathway, in blood pressure regulation and electrolyte homeostasis. PHAII is characterised by high blood pressure associated with the kidneys' failure to process electrolytes such as salt and potassium. Patients respond well to thiazide diuretics.
"Using positional cloning, and aided greatly by the human genome sequence, we identified the mutations on chromosome 12 and 17 that underlie PHAII", explains one of the researchers, Richard Lifton (Yale University, New Haven, CT, USA). "Intriguingly, both of the mutated genes (WNK1 and WNK4) encode members of a novel family of serine-threonine kinases and both localise to the distal nephron. The mutations in these genes that cause PHAII behave as genetic gain-of-function mutations." One of the mutations, hWNK4, lies near a locus on chromosome 17 that has been linked to blood pressure variations in the general population, thereby implicating it in other forms of hypertension (Science 2001; 293: 1107¯12).
Since knowledge of the upstream regulators and downstream targets of these kinases is currently lacking, the authors hope that future research will define the other components of the pathway. Moreover, Lifton adds, such knowledge "may help present new rational targets for development of novel drugs for the treatment of hypertension and congestive heart failure".
Carlos M Ferrario (Wake Forest University, Winston-Salem, NC, USA) says these findings add to the data pointing to a multifactorial basis for essential hypertension and underscore one of the functional pathways involved in raising blood pressure. "While the research was confined to the identification of a gene that may explain a rare form of inheritable hypertension, the data gathered by the authors may assist in exploring the role of this and related genes to the pathogenesis of high blood pressure."
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