Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis
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...
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| Published in | The Journal of clinical investigation Vol. 130; no. 12; pp. 6379 - 6394 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.12.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0021-9738 1558-8238 1558-8238 |
| DOI | 10.1172/JCI94171 |
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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. |
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| AbstractList | 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.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. Gain-of-function mutations in with no lysine (K)1 (WNK1) and WNK4genes 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.sup.+]-[Cl.sup.-] 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. 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. 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. 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. |
| Audience | Academic |
| Author | Chavez-Canales, Maria Migeon, Tiffany O’Shaugnessy, Kevin Unwin, Robert Argaiz, Eduardo R. Grimm, Richard Hureaux, Marguerite Clauser, Eric Loisel-Ferreira, Irmine Thurairajasingam, Nirubiah Rafael, Chloé Abdel-Khalek, Waed Vargas-Poussou, Rosa Kouranti, Ilektra Louis-Dit-Picard, Hélène Mulatero, Paolo Jeunemaitre, Xavier Coleman, Richard Decramer, Stéphane Baron, Stéphanie Hadchouel, Juliette Welling, Paul A. Tack, Ivan Staub, Olivier Do Cruzeiro, Marcio Gamba, Gerardo Vacle, Sarah Roussey, Gwenaëlle Girerd, Xavier |
| AuthorAffiliation | 8 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA 13 Department of Medicine, University of Cambridge, Cambridge, United Kingdom 14 Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy 9 NSERM U1016, Institut Cochin, Paris, France 1 Université de Paris, INSERM, PARCC, F-75006, Paris, France 15 Néphrologie Pédiatrique–Clinique Médicale Pédiatrique, Hôpital Mère Enfant, CHU de Nantes, Nantes, France 16 Service des Explorations Fonctionnelles Physiologiques, CHU de Toulouse et INSERM U1048-I2MC, Toulouse, France 12 AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Unité de Prévention Cardiovasculaire, Hôpital de La Pitié-Salpêtrière, Paris, France 4 Translational Medicine Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, Mexico City, Mexico 7 Department of Pharmacology and Toxico |
| AuthorAffiliation_xml | – name: 1 Université de Paris, INSERM, PARCC, F-75006, Paris, France – name: 14 Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Torino, Italy – name: 18 Departments of Medicine, Nephrology, and Physiology, Johns Hopkins University Medical School, Baltimore, Maryland, USA – name: 10 AP-HP, Département de Génétique, Hôpital Européen Georges Pompidou, Paris, France – name: 2 INSERM UMR_S1155, Tenon Hospital, Paris, France – name: 8 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA – name: 5 Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Mexico City, Mexico – name: 17 UCL Department of Renal Medicine, University College London, Royal Free Campus and Hospital, London, United Kingdom – name: 3 Université Paris-Diderot, Sorbonne Paris Cité, Paris, France – name: 4 Translational Medicine Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, Mexico City, Mexico – name: 7 Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland – name: 12 AP-HP, Institute of Cardiometabolism and Nutrition (ICAN), Unité de Prévention Cardiovasculaire, Hôpital de La Pitié-Salpêtrière, Paris, France – name: 13 Department of Medicine, University of Cambridge, Cambridge, United Kingdom – name: 15 Néphrologie Pédiatrique–Clinique Médicale Pédiatrique, Hôpital Mère Enfant, CHU de Nantes, Nantes, France – name: 6 Service d’Explorations Fonctionnelles, Assistance Publique–Hôpitaux de Paris (AP-HP), F-75015, Paris, France – name: 16 Service des Explorations Fonctionnelles Physiologiques, CHU de Toulouse et INSERM U1048-I2MC, Toulouse, France – name: 9 NSERM U1016, Institut Cochin, Paris, France – name: 11 Service de Néphrologie Pédiatrique, Hôpital des Enfants, Toulouse, France |
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| Keywords | Genetics Nephrology Genetic diseases Protein kinases Epithelial transport of ions and water |
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| Snippet | Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited... Gain-of-function mutations in with no lysine (K)1 (WNK1) and WNK4genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited... Gain-of-function mutations in with no lysine (K) 1 ( WNK1 ) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited... |
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| SubjectTerms | Acidosis Acidosis - genetics Acidosis - metabolism Acidosis - pathology Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Alanine Amino Acid Motifs Animals Asymptomatic Binding sites Biomedical research Blood pressure Causes of Chlorides CRISPR Cullin Cullin Proteins - genetics Cullin Proteins - metabolism Electrolytes Gene mutations Genes Genetic aspects Genetic diversity Genotype & phenotype Health aspects HEK293 Cells Homeostasis Humans Hyperkalemia Hypertension Kidney tubules Kidney Tubules, Distal - metabolism Kidney Tubules, Distal - pathology Kidneys Kinases Life Sciences Lysine Metabolic acidosis Metabolism Mice Mice, Mutant Strains Microfilament Proteins - genetics Microfilament Proteins - metabolism Mutation Oocytes Phenotypes Phosphorylation Physiological aspects Proline Protein kinases Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteins Pseudohypoaldosteronism - genetics Pseudohypoaldosteronism - metabolism Pseudohypoaldosteronism - pathology Ubiquitin Ubiquitin-protein ligase Ubiquitination WNK Lysine-Deficient Protein Kinase 1 - genetics WNK Lysine-Deficient Protein Kinase 1 - metabolism WNK1 gene Xenopus laevis |
| Title | Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis |
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