Trigger 3: PHA2

Question 1

PHA2 can be characterised by

Answer 1

hyperkalemia (>8mmol/l), despite normal GFR, low aldosterone and high blood pressure

• low renin plasma levels
• metabolic acidosis

Question 2

PHA2 is classically caused by mutations in

Answer 2

WNK1/4

Question 3

more recently most PHA2 has been associated with mutations within the

Answer 3

CUL3/KLHL3 domain

Question 4

mutations in WNK1 lead to

Answer 4

increased WNK1 expression

Question 5

mutations in WNK4 are caused by

Answer 5

misses mutation lying in the non-catalytic region of WNK4 protein kinase

Question 6

treated with

Answer 6

TD

Question 7

TD

Answer 7

inhabit NCC co-transporter in DCT

Question 8

WNK1/4 control BP by activating

Answer 8

SPAK/OSR1

Question 9

SPAK/OSR1 modulate acitvity

Answer 9

of ion co-transporer- NCC and NKCC2

Question 10

CUL3/KLHL3 domain is a

Answer 10

ubiquitin E3 ligase

Question 11

CUL3 in CUL3/KLHL3 domain

Answer 11

E3

Question 12

KLHL3 in CUL3/KLHL3 domain

Answer 12

substrate recognition domain

Question 13

what do SPAK/OSR1 interact with

Answer 13

RFQV and RFTI protein motifs on NKCC2 and NCC, directly phosphorylating them

Question 14

NKCC2

Answer 14

RFQV motif- phosphorylated by both T-loop kinase domain and the CCT domain (think diagram)

Question 15

NCC

Answer 15

RFTI motif - phosphorylated by CTT domain

Question 16

mutated CUL3 prevents

Answer 16

E3 activity

Question 17

mutant KLHL3 (most common)

Answer 17

prevent binding to WNK - therefore no Ub

Question 18

basal state WNK4

Answer 18

down regulated: NCC, eNac, Cl- and ROMK

Question 19

ROMK

Answer 19

atp-dpeendnent potassium channel