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

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    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.
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    Date
    2020-08-13
    Journal
    Journal of Clinical Investigation
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/JCI94171
    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. Copyright 2020, American Society for Clinical Investigation.
    Keyword
    hyperkalemic hypertension
    Pseudohypoaldosteronism--genetics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14573
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI94171
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