Pathogenesis of pseudohypoaldosteronism type 2 by WNK1 mutations

Curr Opin Nephrol Hypertens. 2012 Jan;21(1):39-45. doi: 10.1097/MNH.0b013e32834d2fde.


Purpose of review: Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant form of human arterial hypertension, associated with hyperkalemia and hyperchloremic metabolic acidosis. WNK1 and WNK4 are two of the genes mutated in PHA2 patients. This review focuses on the mechanisms by which deletions of the first intron of WNK1 found in PHA2 patients trigger the disease.

Recent findings: The WNK1 gene gives rise to a ubiquitous kinase (L-WNK1) and to a shorter kinase-defective isoform, KS-WNK1 (for kidney-specific WNK1), expressed only in the distal convoluted tubule (DCT) and connecting tubule. WNK1 first intron deletion leads to overexpression of L-WNK1 in the DCT and ubiquitous ectopic expression of KS-WNK1. The increased expression of L-WNK1 in the DCT results in increased activity of the Na-Cl cotransporter (NCC) and thus hypervolemia and hypertension. Contrarily, the mechanisms underlying the hyperkalemia and metabolic acidosis remain unclear.

Summary: As particularly small doses of thiazide diuretics, inhibitors of NCC activity, correct both the blood pressure and metabolic disorders in PHA2 patients, it was believed that increased NCC was directly responsible for all PHA2 features. Studies performed in mouse models of KS-WNK1 inactivation or WNK4-related PHA2, however, have revealed that the situation is much more complex.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acidosis / enzymology
  • Acidosis / genetics
  • Animals
  • Gene Expression Regulation, Enzymologic
  • Genetic Predisposition to Disease
  • Humans
  • Hyperkalemia / enzymology
  • Hyperkalemia / genetics
  • Hypertension / enzymology
  • Hypertension / genetics
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney / drug effects
  • Kidney / enzymology*
  • Minor Histocompatibility Antigens
  • Mutation*
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Pseudohypoparathyroidism / complications
  • Pseudohypoparathyroidism / drug therapy
  • Pseudohypoparathyroidism / enzymology
  • Pseudohypoparathyroidism / genetics*
  • Sodium Chloride Symporter Inhibitors / therapeutic use
  • Sodium Chloride Symporters / metabolism
  • WNK Lysine-Deficient Protein Kinase 1


  • Intracellular Signaling Peptides and Proteins
  • Minor Histocompatibility Antigens
  • Sodium Chloride Symporter Inhibitors
  • Sodium Chloride Symporters
  • Protein Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human

Supplementary concepts

  • Pseudohypoparathyroidism Type 2