Background: Mutations in serine-threonine kinase WNK4 with no lysine (K) at a key catalytic residue cause familial hypertension known as pseudohypoaldosteronism type II (PHAII). The objective of this study was to test whether more subtle changes of WNK4 could be implicated in hypertension or renal failure.
Methods: We screened 956 Japanese patients with hypertension or renal failure for mutations in exons 7 and 17 in the WNK4 gene where the mutations were identified in patients with PHAII.
Results: We identified three novel missense mutations, Met546Val (n = 2) and Pro556Thr (n = 2) in exon 7, and Pro1173Thr (n = 1) in exon 17, in a heterozygous state in addition to four single nucleotide polymorphisms including one synonymous mutation (Ala547Ala). Results of genotyping Met546Val and Pro556Thr mutations indicated that these mutations were not present in a Japanese general population (n = 1875).
Conclusions: The present study indicated that a systematic screening of WNK4 in a large set of patients with hypertension or renal failure detected some rare genetic variants. Although substantial contribution of three novel missense mutations in exons 7 and 17 of WNK4 to the genetics of hypertension or renal failure is still unclear, these mutations in the WNK4 gene identified in Japanese hypertensives but not in a general population may contribute to hypertension and progression of hypertensive complications to some extent.