Table 1.
Genetic mutations found in patients with FHHt
| Gene | Mutation | Mendelian Inheritance | Proposed Mechanism | Corresponding Mouse Model |
|---|---|---|---|---|
| WNK1 | Deletions in intron 1 (4) | Autosomal dominant | Ectopic L-WNK1 expression specifically in the DCT (58) | Wnk1FHHt/+ (intron 1 deletion) (58) |
| Acidic domain missense mutations: E631K, A634T, D635E, D635N, Q636E, Q636R (59) | Autosomal dominant | Decreased KS-WNK1 degradation in the DCT (59) | Wnk1delE631/+ (59) | |
| WNK4 | Acidic domain missense mutations: E562K, D564A, Q565E (4), D564H (60), P561L (61), and E560G (62) | Autosomal dominant | Decreased WNK4 degradation in the DCT (20) | Wnk4+/+/Q562E/Q562E (63); Wnk4D561A/+ (64) |
| COOH-terminal missense mutations: R1185C (4) and K1169E (65) | Autosomal dominant | Disruption of the inhibitory domain, promoting increased WNK4 activity (45) | Not reported yet | |
| KLHL3 | Several missense mutations (16,17) | Autosomal dominant | Decreased WNK4/KS-WNK1 degradation in the DCT (66,67) | Klhl3R528H/+ (66);Klhl3M131V/+ (68) |
| Several missense mutations (16,17) as well as nonsense mutations and splicing-altering mutations (16) | Autosomal recessive | Decreased WNK4/KS-WNK1 degradation in the DCT (69) | Klhl3-/- (69) | |
| CUL3 | Mutations in sites implicated in splicing of exon 9: intron 8 splice acceptor, intron 9 splice donor, putative intron 8 splice branch site, and a putative splice enhancer in exon 9 (12) | Autosomal dominant | Decreased WNK4/KS-WNK1 degradation in the DCT (70); impaired vascular relaxation through activation of the RhoA-ROCK pathway (71) | Cul3Δ403-459/+ (72);Cul3Het/Δ9 (70); pgk-Cul3Δ9 (71) |
WNK, with no lysine kinase; KLH3, Kelch-like family member 3; CUL3, cullin 3; L-WNK1, full-length with WNK1; KS-WNK1 kidney-specific WNK1; DCT, distal convoluted tubule; ROCK, Rho kinase; FHHt, familial hyperkalemic hypertension.