WNK4

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. 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. Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity.

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. WNK4 protein is highly expressed in the distal convoluted tubule (DCT) and the cortical collecting duct (CCD) of the kidney. WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species.

Gene mutations in WNK4 has been found in patients with pseudohypoaldosteronism type II (PHAII), also known as familial hyperkalemic hypertension (FHHt) or Gordon syndrome. 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).