ArticleThe Journal of clinical investigation2020
Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 46 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System.Cells · 2026Review
- Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates.The Journal of clinical investigation · 2025Article
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Ubiquitination-mediated protein homeostasis in cardiovascular diseases: molecular mechanisms and therapeutic opportunities.American journal of cardiovascular disease · 2025Review
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Distal convoluted tubule-specific disruption of the COP9 signalosome but not its regulatory target cullin 3 causes tubular injury.American journal of physiology. Renal physiology · 2024Article
- Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance.American journal of physiology. Renal physiology · 2024Article
- A New Phase for WNK Kinase Signaling Complexes as Biomolecular Condensates.Physiology (Bethesda, Md.) · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- KS-WNK1 is required for the renal response to extreme changes in potassium intake.American journal of physiology. Renal physiology · 2024Article
- Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation.American journal of physiology. Renal physiology · 2024Article
- Expression of the kidney anion exchanger 1 affects WNK4 and SPAK phosphorylation and results in claudin-4 phosphorylation.Heliyon · 2023Article
- Thirty years of the NaCl cotransporter: from cloning to physiology and structure.American journal of physiology. Renal physiology · 2023Review
- Article
- Dietary anions control potassium excretion: it is more than a poorly absorbable anion effect.American journal of physiology. Renal physiology · 2023Article
- Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension.Hypertension (Dallas, Tex. : 1979) · 2023Review
- Control of sodium and potassium homeostasis by renal distal convoluted tubules.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2023Article
- Blood pressure effects of sodium transport along the distal nephron.Kidney international · 2022Review
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Authors and funding
29 authors at 12 institutions in 6 countries.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.