Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis
Author
Louis-Dit-Picard, H.Kouranti, I.
Rafael, C.
Loisel-Ferreira, I.
Chavez-Canales, M.
Abdel-Khalek, W.
Argaiz, E.R.
Baron, S.
Vacle, S.
Migeon, T.
Coleman, R.
Cruzeiro, M.D.
Hureaux, M.
Thurairajasingam, N.
Decramer, S.
Girerd, X.
O�Shaugnessy, K.
Mulatero, P.
Roussey, G.
Tack, I.
Unwin, R.
Vargas-Poussou, R.
Staub, O.
Grimm, R.
Welling, P.A.
Gamba, G.
Clauser, E.
Hadchouel, J.
Jeunemaitre, X.
Date
2020-08-13Journal
Journal of Clinical InvestigationPublisher
American Society for Clinical InvestigationType
Article
Metadata
Show full item recordAbstract
Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3–Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK’s cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values”Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine–rich kinase–Na+-Cl– cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis. Copyright 2020, American Society for Clinical Investigation.Identifier to cite or link to this item
http://hdl.handle.net/10713/14573ae974a485f413a2113503eed53cd6c53
10.1172/JCI94171
Scopus Count
Collections
Related articles
- Role of KLHL3 and dietary K<sup>+</sup> in regulating KS-WNK1 expression.
- Authors: Ostrosky-Frid M, Chávez-Canales M, Zhang J, Andrukhova O, Argaiz ER, Lerdo-de-Tejada F, Murillo-de-Ozores A, Sanchez-Navarro A, Rojas-Vega L, Bobadilla NA, Vazquez N, Castañeda-Bueno M, Alessi DR, Gamba G
- Issue date: 2021 May 1
- The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
- Authors: Ohta A, Schumacher FR, Mehellou Y, Johnson C, Knebel A, Macartney TJ, Wood NT, Alessi DR, Kurz T
- Issue date: 2013 Apr 1
- Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice.
- Authors: Guo Q, Zhang Y, Jiang GR, Zhang C
- Issue date: 2021 Feb
- Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice.
- Authors: Maeoka Y, Ferdaus MZ, Cornelius RJ, Sharma A, Su XT, Miller LN, Robertson JA, Gurley SB, Yang CL, Ellison DH, McCormick JA
- Issue date: 2022 Mar
- ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation.
- Authors: Murthy M, Kurz T, O'Shaughnessy KM
- Issue date: 2016 Jul