Table 1.

FHHt mutations and their effects on the affected genes

Gene	Effect	Result	Effect on the encoded protein	References
WNK1	Deletion of intron I	↑ WNK1 expression	↑ L-WNK1 expression	[14, 25]
WNK4	Missense mutation in the acidic motif	↑ WNK4 expression due to disruption in the KLHL3 recognition site	↑ WNK4	[14, 15, 17, 81]
WNK4	R1185C mutation in the C-terminal domain	Disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites	Unknown	[26, 27]
KLHL3	Missense mutations in the BTB or BACK domain	Disruption of the CUL3–KLHL3 interaction	↑ WNK1 ↑ WNK4 ↑ WNK3	[15, 17, 18, 81, 82]
	Missense mutations in the Kelch propeller blades	Disruption of the substrate (WNK) binding	↑ WNK1 ↑ WNK4 ↑ WNK3
CUL3	Exon 9 deletion	Increased KLHL3 ubiquitination and degradation	↓KLHL3 ↑ WNK1 ↑ WNK4 ↑ WNK3	[15, 17, 86]
		Altered CUL3 flexibility leading to CUL3 auto-degradation and prevention of WNK ubiquitination		[16]

↑ indicates increase, ↓ indicates decrease