Published Online
on July 5, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on March 21, 2005
Revised on April 13, 2005

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; and 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.).

^* To whom correspondence should be addressed. E-mail: kmo22{at}medschl.cam.ac.uk.

Abstract--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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