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. Author manuscript; available in PMC: 2010 Sep 30.
Published in final edited form as: Curr Opin Nephrol Hypertens. 2009 Sep;18(5):421–427. doi: 10.1097/MNH.0b013e32832f2fcb

Figure 1.

Figure 1

Contrasting theories into the mechanism of FHHt mutations. A. Mutant WNK4 as a Loss of Function. WNK4 acts to inhibit NCC activity. Mutant WNK4 is unable to inhibit NCC, resulting in a net increase in NCC activity. B. Mutant WNK4 as a Gain of Function. In the normal state, WNK4 activates OSR1/SPAK, which in turn activates NCC, resulting in enhanced NCC activity. The mutant WNK4 is a gain of function mutation, resulting in increased OSR1/SPAK activation and therefore increased NCC activity. C. Mutant WNK1 acting via WNK4. WNK1 normally acts to inhibit WNK4. Since WNK4 inhibits NCC, this has the net result of increasing NCC activity. Mutant WNK1 is a gain of function, enhancing its ability to inhibit WNK4 and therefore increasing NCC activity. D. Mutant WNK1 Acting Via OSR1/SPAK. WNK1 normally acts to increase OSR1/SPAK phosphorylation, which increases NCC activity. Mutant WNK1 is a gain of function mutation, resulting in increased OSR1/SPAK activity, which in turn increases NCC activity.