FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction.
Furthermore, an intact STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4 PHAII mutation to increase NCC phosphorylation and blood pressure in mice.
Furthermore, an intact STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4 PHAII mutation to increase NCC phosphorylation and blood pressure in mice.
Furthermore, an intact STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4PHAII mutation to increase NCC phosphorylation and blood pressure in mice.
Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII).
Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII).
Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity.
Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion.
Germline mutations in the WNK4 gene originate Gordon syndrome or pseudohypoaldosteronism type II, a familial form of hypertension with hyperkalemia and hypercalciuria.
However, mutations in WNK1/4 are present in a small minority of GS families, and further genes have emerged (CUL3 and KLHL3) that code for Cullin-3 (a scaffold protein in an ubiquitin-E3 ligase) and an adaptor protein, Kelch3, respectively.
Hyperkalemic RTA accompanied by hypertension (pseudohypoaldosteronism type 2 [PHA2]) is caused by dominant gain-of-function mutations in the kinases WNK1 and WNK4.
Hyperkalemic RTA accompanied by hypertension (pseudohypoaldosteronism type 2 [PHA2]) is caused by dominant gain-of-function mutations in the kinases WNK1 and WNK4.
Hyperkalemic RTA accompanied by hypertension (pseudohypoaldosteronism type 2 [PHA2]) is caused by dominant gain-of-function mutations in the kinases WNK1 and WNK4.
In summary, Klhl3<sup>M131V/+</sup> KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.-Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.
In summary, Klhl3<sup>M131V/+</sup> KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.-Lin, C.-M., Cheng, C.-J., Yang, S.-S., Tseng, M.-H., Yen, M.-T., Sung, C.-C., Lin, S.-H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain.
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension.