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Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis
Hélène Louis-Dit-Picard, … , Juliette Hadchouel, Xavier Jeunemaitre
Hélène Louis-Dit-Picard, … , Juliette Hadchouel, Xavier Jeunemaitre
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(12):6379-6394. https://doi.org/10.1172/JCI94171.
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Research Article Genetics Nephrology

Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis

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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.

Authors

Hélène Louis-Dit-Picard, Ilektra Kouranti, Chloé Rafael, Irmine Loisel-Ferreira, Maria Chavez-Canales, Waed Abdel-Khalek, Eduardo R. Argaiz, Stéphanie Baron, Sarah Vacle, Tiffany Migeon, Richard Coleman, Marcio Do Cruzeiro, Marguerite Hureaux, Nirubiah Thurairajasingam, Stéphane Decramer, Xavier Girerd, Kevin O’Shaugnessy, Paolo Mulatero, Gwenaëlle Roussey, Ivan Tack, Robert Unwin, Rosa Vargas-Poussou, Olivier Staub, Richard Grimm, Paul A. Welling, Gerardo Gamba, Eric Clauser, Juliette Hadchouel, Xavier Jeunemaitre

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Figure 7

The DCTs of Wnk1+/delE631 mice contain large WNK bodies.

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The DCTs of Wnk1+/delE631 mice contain large WNK bodies.
(A) Immunofluor...
(A) Immunofluorescence experiments using WNK1 and NCC antibodies. While only small puncta are observed in Wnk1+/+ DCT, large WNK1-positive structures are found in Wnk1+/delE631 DCT, resembling the previously described WNK bodies. Scale bar: 10 μm. (B) Costaining with NCC, AQP2, and NKCC2 revealed that these bodies are localized in the DCT and CNT/CCD, but not in Henle’s loop. Scale bar: 20 μm.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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