The WNK4 gene provides instructions for making a protein that plays a role in blood pressure regulation by helping control the amount of sodium and potassium in the body. The WNK4 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions.
The WNK4 protein regulates channels in the cell membrane that control the transport of sodium or potassium into and out of cells, which occurs primarily in the kidneys. Sodium channels help transport sodium into specialized kidney cells, which then transfer it into the blood. This transfer helps keep sodium in the body through a process called reabsorption. Potassium channels handle excess potassium that has been transferred from the blood into the kidney cells. The channels transport the potassium out of the cells in a process called secretion, so that it can be removed from the body in the urine. The WNK4 protein is able to promote sodium reabsorption and block potassium secretion. Depending on conditions in the cell, the WNK4 protein is also able to block (inhibit) sodium reabsorption.
Health Conditions Related to Genetic Changes
Pseudohypoaldosteronism type 2
At least eight mutations in the WNK4 gene have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). The mutations involved in this condition change single protein building blocks (amino acids) in the WNK4 protein. The alterations to the WNK4 protein impair its breakdown, resulting in higher than normal levels of WNK4 protein and elevated WNK4 activity. The increase in WNK4 activity leads to increased sodium reabsorption and reduced potassium secretion, resulting in hypertension and hyperkalemia.More About This Health Condition
Studies have associated normal variations in the WNK4 gene with an increased risk of high blood pressure (hypertension) in people without pseudohypoaldosteronism type 2. A combination of genetic variations and environmental factors likely influence the development of this complex condition.
Other Names for This Gene
- protein kinase lysine-deficient 4
- protein kinase with no lysine 4
- serine/threonine-protein kinase WNK4
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Gamba G. Regulation of the renal Na+-Cl- cotransporter by phosphorylation and ubiquitylation. Am J Physiol Renal Physiol. 2012 Dec 15;303(12):F1573-83. doi: 10.1152/ajprenal.00508.2012. Epub 2012 Oct 3. Citation on PubMed or Free article on PubMed Central
- Kokubo Y, Kamide K, Inamoto N, Tanaka C, Banno M, Takiuchi S, Kawano Y, Tomoike H, Miyata T. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. J Hum Genet. 2004;49(9):507-515. doi: 10.1007/s10038-004-0181-0. Epub 2004 Aug 11. Citation on PubMed
- Ohta A, Schumacher FR, Mehellou Y, Johnson C, Knebel A, Macartney TJ, Wood NT, Alessi DR, Kurz T. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 2013 Apr 1;451(1):111-22. doi: 10.1042/BJ20121903. Citation on PubMed or Free article on PubMed Central
- Ring AM, Cheng SX, Leng Q, Kahle KT, Rinehart J, Lalioti MD, Volkman HM, Wilson FH, Hebert SC, Lifton RP. WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4020-4. doi: 10.1073/pnas.0611727104. Epub 2007 Feb 26. Citation on PubMed or Free article on PubMed Central
- Subramanya AR, Liu J, Ellison DH, Wade JB, Welling PA. WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction. J Biol Chem. 2009 Jul 3;284(27):18471-80. doi: 10.1074/jbc.M109.008185. Epub 2009 Apr 28. Citation on PubMed or Free article on PubMed Central
- Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human hypertension caused by mutations in WNK kinases. Science. 2001 Aug 10;293(5532):1107-12. doi: 10.1126/science.1062844. Citation on PubMed
- Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4. doi: 10.1073/pnas.242735399. Epub 2003 Jan 6. Citation on PubMed or Free article on PubMed Central