A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene

Hypertension. 2005 Aug;46(2):295-300. doi: 10.1161/01.HYP.0000174326.96918.d6. Epub 2005 Jul 5.


We identified a new kindred with the familial syndrome of hypertension and hyperkalemia (pseudohypoaldosteronism type II or Gordon's syndrome) containing an affected father and son. Mutation analysis confirmed a single heterozygous G to C substitution within exon 7 (1690G>C) that causes a missense mutation within the acidic motif of WNK4 (564D>H). We confirmed the function of this novel mutation by coexpressing it in Xenopus oocytes with either the NaCl cotransporter (NCCT) or the inwardly rectifying K-channel (ROMK). Wild-type WNK4 inhibits 22Na+ flux in Xenopus oocytes expressing NCCT by approximately 90% (P<0.001), whereas the 564D>H mutant had no significantly inhibitory effect on flux through NCCT. In oocytes expressing ROMK, wild-type WNK4 produced >50% inhibition of steady-state current through ROMK at a +20-mV holding potential (P<0.001). The 564D>H mutant produced further inhibition with steady-state currents to some 60% to 70% of those seen with the wild-type WNK4. Using fluorescent-tagged NCCT (enhanced cyan fluorescent protein-NCCT) and ROMK (enhanced green fluorescent protein-ROMK) to quantify the expression of the proteins in the oocyte membrane, it appears that the functional effects of the 564D>H mutation can be explained by alteration in the surface expression of NCCT and ROMK. Compared with wild-type WNK4, WNK4 564D>H causes increased cell surface expression of NCCT but reduced expression of ROMK. This work confirms that the novel missense mutation in WNK4, 564D>H, is functionally active and highlights further how switching charge on a single residue in the acid motif of WNK4 affects its interaction with the thiazide-sensitive target NCCT and the potassium channel ROMK.

Publication types

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

MeSH terms

  • Adult
  • Amino Acid Motifs
  • Animals
  • Aspartic Acid
  • Cell Membrane / metabolism
  • Female
  • Genetic Testing
  • Histidine
  • Humans
  • Hyperkalemia / etiology
  • Hypertension / etiology
  • Male
  • Mutation, Missense*
  • Oocytes / metabolism
  • Pedigree
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Pseudohypoaldosteronism / complications
  • Pseudohypoaldosteronism / genetics*
  • Pseudohypoaldosteronism / physiopathology
  • Receptors, Drug / metabolism
  • Sodium Chloride Symporters / metabolism
  • Sodium Radioisotopes / pharmacokinetics
  • Xenopus laevis


  • KCNJ1 protein, human
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sodium Chloride Symporters
  • Sodium Radioisotopes
  • thiazide receptor
  • Aspartic Acid
  • Histidine
  • Protein Serine-Threonine Kinases
  • WNK4 protein, human