WNK1/WNK4 mutations

Question 1

What gene mutations can cause PHAII?

Answer 1

WNK1
WNK4
CUL3
KLHL3

Question 2

How does normal WNK1/4 function affect the NCC?

Answer 2

Phosphorylates SPAK/OSR1 which phosphorylates NCC, targeting it for lysosomal degradation
(decreasing salt retention= decreased water retention)

Question 3

How do WNK1/WNK4 mutations cause hypertension?

Answer 3

1. Loss of control of NCC
2. Na+ drawn in through NCC due to gradient created by Na+ K+ ATPase on basolateral membrane of renal epithelial cell –> Na+ reabsorbed into blood
3. Cl- cotransported through NCC and reabsorbed by blood via chloride channel Kb (voltage-gated chloride channel)
4. High Na+ Cl- conc in blood causes increased water reabsorption in PCT/descending limb of LoH/ CD
5. Increased blood volume= increased blood pressure