Serine/threonine protein kinase WNK4 also known as With No lysine (K) protein kinase 4 (WNK4), is an enzyme that in humans is encoded by the WNK4 gene.[5] Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome or Familial Hyperkalemic Hypertension.
WNK4 is a member of a serine/threonine kinase family that comprises four members. The family is so named because unlike other serine/threonine kinases, WNKs are characterized by the lack of the lysine in the subdomain II of the catalytic domain.[6] Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity.[6]
In humans, the WNK4 gene is located on chromosome 17q21-q22. It produces a 1,243-amino acid protein encoded by a 3,732-nucleotide open reading frame within a 4 kb cDNA transcript.[7] WNK4 protein is highly expressed in the distal convoluted tubule (DCT) and the cortical collecting duct (CCD) of the kidney.[7] WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species.[8][9][10]
Gene mutations in WNK4 has been found in patients with pseudohypoaldosteronism type II (PHAII),[7] also known as familial hyperkalemic hypertension (FHHt)[11] or Gordon syndrome.[12] PHAII is an autosomal dominant hereditary disease characterized by hyperkalemia, hypertension, and metabolic acidosis. WNK4 plays a critical role in the regulation of various ion transporters and channels in the kidney. PHAII-causing mutations in WNK4 result in the dysregulation of renal sodium and potassium transporters and channels, leading to defects in sodium and potassium retention by the kidney, and in turn, elevated blood pressure and potassium concentration in the blood (hyperkalemia).
- ^ a b c GRCh38: Ensembl release 89: ENSG00000126562 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035112 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: WNK4 WNK lysine deficient protein kinase 4".
- ^ a b Xu B, English JM, Wilsbacher JL, Stippec S, Goldsmith EJ, Cobb MH (June 2000). "WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II". The Journal of Biological Chemistry. 275 (22): 16795–801. doi:10.1074/jbc.275.22.16795. PMID 10828064.
- ^ a b c Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. (August 2001). "Human hypertension caused by mutations in WNK kinases". Science. 293 (5532): 1107–12. doi:10.1126/science.1062844. PMID 11498583. S2CID 22700809.
- ^ Kahle KT, Gimenez I, Hassan H, Wilson FH, Wong RD, Forbush B, et al. (February 2004). "WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia". Proceedings of the National Academy of Sciences of the United States of America. 101 (7): 2064–9. doi:10.1073/pnas.0308434100. PMC 357052. PMID 14769928.
- ^ Veríssimo F, Jordan P (September 2001). "WNK kinases, a novel protein kinase subfamily in multi-cellular organisms". Oncogene. 20 (39): 5562–9. doi:10.1038/sj.onc.1204726. PMID 11571656.
- ^ Murillo-de-Ozores AR, Rodríguez-Gama A, Bazúa-Valenti S, Leyva-Ríos K, Vázquez N, Pacheco-Álvarez D, et al. (August 2018). "C-terminally truncated, kidney-specific variants of the WNK4 kinase lack several sites that regulate its activity". The Journal of Biological Chemistry. 293 (31): 12209–12221. doi:10.1074/jbc.RA118.003037. PMC 6078442. PMID 29921588.
- ^ Arnold JE, Healy JK (September 1969). "Hyperkalemia, hypertension and systemic acidosis without renal failure associated with a tubular defect in potassium excretion". The American Journal of Medicine. 47 (3): 461–72. doi:10.1016/0002-9343(69)90230-7. PMID 5808659.
- ^ Gordon RD, Geddes RA, Pawsey CG, O'Halloran MW (November 1970). "Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction". Australasian Annals of Medicine. 19 (4): 287–94. doi:10.1111/imj.1970.19.4.287. PMID 5490655.