Table 2.
Genetically modified mouse models with altered WNK4 expression/function
| Mouse Model | Mutation | Effect on Protein Function and/or Levels | Phenotype | Original Report |
|---|---|---|---|---|
| Transgenic WNK4+/+/Q562E/Q562E | Two additional copies of the WNK4 gene harboring FHHt mutation Q562E (equivalent to Q565E in human WNK4) | Higher WNK4 levels (19) | FHHt-like: increased blood pressure, hyperkalemia, metabolic acidosis, and hypercalciuria as well as DCT hyperplasia | (63) |
| WNK4D561A/+ | D561A (equivalent to D564A in human WNK4) | Higher WNK4 levels, due to decreased degradation (20) | FHHt-like: increased blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, higher NCC levels, and phosphorylation | (64) |
| WNK4 hypomorphic | Exon 7 deletion | Abnormal splicing between exons 6 and 9, with a protein lacking 14 kDa in the middle portion. WNK4ΔEx7-8 has decreased kinase activity | Gitelman-like: lower blood pressure and decreased OSR1 and NCC phosphorylation | (74) |
| WNK4-/- | Deletion of exon 1 | Absent WNK4 expression | Gitelman-like: hypokalemia, hypochloremic metabolic alkalosis, hypomagnesemia, increased plasma renin activity; virtually absent NCC phosphorylation and lower NCC levels (both at mRNA and protein levels) | (14) |
| Transgenic (WNK4WT) | Additional copies of WNK4 (2 copies or 30 extra copies) | Higher WNK4 protein levels | FHHt-like: high blood pressure, hyperkalemia with hyperchloremic metabolic acidosis, higher SPAK, OSR1 and NCC expression. and phosphorylation | (20) |
| WNK4-/- | Deletion of exon 2 | Absent WNK4 expression | Gitelman-like: lower blood pressure while on a low-NaCl diet and decreased SPAK and NCC expression and phosphorylation | (15) |
| WNK4-/- | Deletion of exons 1 and 2 | Absent WNK4 expression | Gitelman-like: lower NCC expression and phosphorylation | (75) |
| WNK4L319F,L321F/L319F,L321F | L319F and L321F | Cl−-insensitive WNK4 and therefore, constitutively active kinase | FHHt-like: increased blood pressure, higher plasma K+ concentration, and hyperchloremic metabolic acidosis, with higher NCC expression and phosphorylation | (76) |
WNK, with no lysine kinase; FHHt, familial hyperkalemic hypertension; DCT, distal convoluted tubule; NCC, NaCl cotransporter; OSR1, oxidative stress-responsive 1; SPAK, STE20/SPS1-related proline-alanine-rich protein kinase.