In 2001, four missense mutations in the WNK4 gene were identified in patients with pseudohypoaldosteronism type 2 (PHAII) (Fig. 1). Three of these mutations (E562K, D564A, and Q565E) are charge-changing substitutions in the acidic motif of WNK4, which are conserved among all members of the WNK family in human and rodent species. The fourth substitution (R1185C) is located in the calmodulin-binding domain near the second coiled-coil domain. Few other PHAII mutations in WNK4 have also been reported. Examples of these mutations include E560G, P561L,  and D564H, all of which are located close to or in the acidic motif; and K1169E which is located between the coiled-coil 2 and the calmodulin-binding domain.
