ArticleHuman molecular genetics2019
OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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40 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Dent disease: clinical practice recommendations.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2025Guideline
- Megalin: from structure to function.Nature reviews. Nephrology · 2026Review
- Lipid turnover and GEF recruitment collectively determine Rab5 recruitment and activation during the first step of early endosome formation.Nature communications · 2026Article
- Identification of Two Novel Variants inHuman mutation · 2026Article
- Bleeding and hemostatic defects in Lowe syndrome: the role of OCRL in platelets.Frontiers in cell and developmental biology · 2026Review
- Enhanced Notch dependent gliogenesis and delayed physiological maturation underlie neurodevelopmental defects in Lowe syndrome.EMBO molecular medicine · 2025Article
- High-throughput marker-free screening of cytoplasmic vacuoles in adherent cells via Fourier ptychographic microscopy.Biomedical optics express · 2025Article
- Dysregulation of Inositol Polyphosphate 5-Phosphatase OCRL in Alzheimer's Disease: Implications for Autophagy Dysfunction.International journal of molecular sciences · 2025Article
- Protein handling in kidney tubules.Nature reviews. Nephrology · 2025Review
- Modelling Lowe syndrome and Dent-2 disease using zebrafish.Frontiers in cell and developmental biology · 2025Review
- Probing and imaging phospholipid dynamics in live cells.Life metabolism · 2024Review
- Atypical phenotypes and novel OCRL variations in southern Chinese patients with Lowe syndrome.Pediatric nephrology (Berlin, Germany) · 2024Article
- OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses.Biomolecules · 2024Article
- WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.Molecular biology of the cell · 2024Article
- WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.bioRxiv : the preprint server for biology · 2024Article
- Challenges and opportunities for discovering the biology of rare genetic diseases of the brain.Journal of biosciences · 2024Review
- A missense mutant of ocrl1 promotes apoptosis of tubular epithelial cells and disrupts endocytosis and the cell cycle of podocytes in Dent-2 Disease.Cell communication and signaling : CCS · 2023Article
- Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes.Biomolecules · 2023Article
- IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system.Frontiers in behavioral neuroscience · 2023Review
- Emerging roles of proximal tubular endocytosis in renal fibrosis.Frontiers in cell and developmental biology · 2023Review
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/- mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/- kidneys. The OcrlY/- mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5-bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/- mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/- and Clcn5Y/- mice suggest shared mechanisms in Dent diseases 1 and 2. These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.
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