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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 8

Abnormal K+ handling in Wnk1+/delE631 mice.

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Abnormal K+ handling in Wnk1+/delE631 mice.
(A–C) Decreased UK+ excretio...
(A–C) Decreased UK+ excretion, Uk/Pk ratio, and TTKG. (A) Urinary K+ excretion was lower in Wnk1+/delE631 (n = 7, 52 ± 5.3 mmol/mmol creatinine) than in Wnk1+/+ mice (n = 7, 69.3 ± 7.9 mmol/mmol creatinine). *P < 0.05, unpaired Student’s t test. (B) Basal urinary/plasma ratio of K+ concentration was lower in Wnk1+/delE631 (n = 24, 37.2 ± 2.1) than in Wnk1+/+ mice (n = 24, 56.3 ± 3.8). ***P < 0.0001, unpaired Student’s t test. (C) TTKG was significantly lower in Wnk1+/delE631 (n = 24, 8.6 ± 0.3) than in Wnk1+/+ mice (n = 24, 10.1 ± 0.3). ***P = 0.0003. Following 4-day HCTZ oral (240 mg/kg/d) administration, the difference in TTKG between Wnk1+/+ and Wnk1+/delE631 remained the same (9.5 ±0.9 versus 11.8 ±0.8, respectively) although no more significant (P = 0.068), likely because of the smaller number of animals studied (n = 9 and n = 11, respectively). Statistical comparisons were made using unpaired t tests. (D) ENaC expression. Representative immunoblots with the indicated antibodies performed on the membrane-enriched fractions of the renal cortex of mice of each genotype. Densitometric analysis. The abundance of the cleaved form of the α-subunit of ENaC was significantly increased in Wnk1+/delE631 mice compared with Wnk1+/+ mice. The expression level in Wnk1+/+ mice was arbitrarily set to 100. Data are represented as mean ± SEM.*P < 0.05, unpaired Student’s t test. (E and F) Natriuretic and kaliuretic response to amiloride. Urinary Na+ (E) and K+ (F) excretion in response to amiloride injection. Wnk1+/+ and Wnk1+/delE631 males (n = 7 in each group) were housed in metabolic cages and received 1 injection of vehicle or amiloride on 2 consecutive days. Urine was collected 6 hours after injection. Data are represented as mean ± SEM. *P < 0.05; **P< 0.01; ****P < 0.0001 versus vehicle, unpaired Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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