ArticleEMBO molecular medicine2015
Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia.
Article in EMBO molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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68 citing papers in PubMed, 101 citations in OpenAlex.
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II.Endocrine · 2025Article
- Role of the Renin-Angiotensin System in Blood Pressure Regulation in Smooth Muscle-Specific Cullin-3 Deficient Mice.Hypertension (Dallas, Tex. : 1979) · 2025Article
- CSN-CRL Complexes: New Regulators of Adipogenesis.Biomolecules · 2025Review
- The evolving concepts of KS-WNK1 effect on NCC activity.American journal of physiology. Renal physiology · 2025Review
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Genome-wide association study of subfoveal choroidal thickness in a longitudinal cohort of older adults.Scientific reports · 2024Article
- Article
- 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
- A New Phase for WNK Kinase Signaling Complexes as Biomolecular Condensates.Physiology (Bethesda, Md.) · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- The role ofJournal of pharmaceutical analysis · 2023Review
- Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.Cell communication and signaling : CCS · 2023Review
- Cullin 3 and Blood Pressure Regulation: Insights From Familial Hyperkalemic Hypertension.Hypertension (Dallas, Tex. : 1979) · 2023Review
- Ubiquitination of NKCC2 by the cullin-RING E3 ubiquitin ligase family in the thick ascending limb of the loop of Henle.American journal of physiology. Renal physiology · 2023Article
- Aldosterone defects in infants and young children with hyperkalemia: A single center retrospective study.Frontiers in pediatrics · 2023Article
- Cullin 3 mutant causing familial hyperkalemic hypertension lacks normal activity in the kidney.American journal of physiology. Renal physiology · 2022Article
- Kelch-like protein 3 in human disease and therapy.Molecular biology reports · 2022Review
8 more citing papers are in PubMed but not listed here.
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15 authors at 4 institutions in 2 countries.
Funding
Abstract
Deletion of exon 9 from Cullin-3 (CUL3, residues 403-459: CUL3(Δ403-459)) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin-RING-ubiquitin-ligase complexes. Bound to KLHL3, CUL3-RBX1 ubiquitylates WNK kinases, promoting their ubiquitin-mediated proteasomal degradation. Since WNK kinases activate Na/Cl co-transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin-RING-ligase formation. We report here that the PHA2E mutant, CUL3(Δ403-459), is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3(Δ403-459) auto-ubiquitylates and loses interaction with two important Cullin regulators: the COP9-signalosome and CAND1. A novel knock-in mouse model of CUL3(WT) (/Δ403-459) closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.
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