Novel missense mutations of WNK1 in patients with hypokalemic salt‐losing tubulopathies. (27th September 2012)

• Record Type: Journal Article
• Authors: Zhang, C; Zhu, Y; Huang, F; Jiang, G; Chang, J; Li, R
• Is Part Of: Clinical genetics. Volume 83:Number 6(2013:Jun.)
• Page Start: 545
• Page End: 552
• Publication Date: 2012-09-27
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12008
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>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 <italic>CLCNKB</italic> or <italic>SLC12A3</italic>. 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, <italic>de novo</italic> and inherited, respectively. One of these WNK1 mutations was shown to reduce NCC protein membrane expression <italic>in vitro</italic> 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.</p> </abstract>