The authors declare that there are no conflicts of interest.
Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies
Article first published online: 27 SEP 2012
© 2012 John Wiley & Sons A/S
Volume 83, Issue 6, pages 545–552, June 2013
How to Cite
Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies., , , , , .
- Issue published online: 23 APR 2013
- Article first published online: 27 SEP 2012
- Accepted manuscript online: 30 AUG 2012 01:08PM EST
- Manuscript Revised: 28 AUG 2012
- Manuscript Accepted: 28 AUG 2012
- Manuscript Received: 3 APR 2012
- Foundation of Science and Technology Commission of Shanghai Municipality. Grant Number: 114119a9900
- Innovation Program of Shanghai Municipal Education Commission. Grant Number: 10YZ41
- salts-losing tubulopathy ;
- WNK kinases
Clinical and genetic studies have suggested that a loss of function and gain of function mutation in the same gene can cause different diseases. The aim of this study was to test the hypothesis that inactivating mutations in WNK1 (with no K (lysine) protein kinase-1) or WNK4 could be a new candidate for causing hypokalemic salt-losing tubulopathy (SLT) in those patients with unknown genetic defects because SLT is the opposite phenotype to pseudohypoaldosteronism type II (PHAII). We screened 44 SLTs patients and found that 33 (75%) cases had homozygous or compound heterozygous mutations in CLCNKB or SLC12A3. Two novel missense mutations were identified in WNK1, but not in WNK4, in 2 of the remaining 11 patients. The WNK1 mutations occurred in the protein C-terminus domain, de novo and inherited, respectively. One of these WNK1 mutations was shown to reduce NCC protein membrane expression in vitro because of impairing the suppressive effect of WNK4-mediated inhibition. Taken together, our findings suggest that inactivating mutations in WNK1 may cause SLT, a phenotype opposite to that of PHAII caused by WNK1 intronic deletion.