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(Hypertension. 2005;46:295.)
© 2005 American Heart Association, Inc.

Original Articles

A New Kindred With Pseudohypoaldosteronism Type II and a Novel Mutation (564D>H) in the Acidic Motif of the WNK4 Gene

Amir P. Golbang; Meena Murthy; Abbas Hamad; Che-Hsiung Liu; Georgina Cope; William Van’t Hoff; Alan Cuthbert; Kevin M. O’Shaughnessy

From the Clinical Pharmacology Unit, and the Department of Medicine (M.M., A.C.), University of Cambridge, United Kingdom; and NephroUrology Unit, Great Ormond Street Hospital, London, United Kingdom (W.V.H.).

Correspondence to Dr K.M. O’Shaughnessy, Clinical Pharmacology Unit Level 6, ACCI Box 110, Addenbrooke’s Hospital Cambridge, CB2 2QQ, UK. E-mail kmo22{at}medschl.cam.ac.uk

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 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.

Key Words: kinase • mutation

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