OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease
© The Author(s) 2018. Published by Oxford University Press..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Human molecular genetics - 28(2019), 12 vom: 15. Juni, Seite 1931-1946 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Festa, Beatrice Paola [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.02.2020 Date Revised 09.03.2020 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/hmg/ddy449 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM292197756 |
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| 100 | 1 | |a Festa, Beatrice Paola |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 06.02.2020 | ||
| 500 | |a Date Revised 09.03.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2018. Published by Oxford University Press. | ||
| 520 | |a 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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| 700 | 1 | |a Berquez, Marine |e verfasserin |4 aut | |
| 700 | 1 | |a Gassama, Alkaly |e verfasserin |4 aut | |
| 700 | 1 | |a Amrein, Irmgard |e verfasserin |4 aut | |
| 700 | 1 | |a Ismail, Hesham M |e verfasserin |4 aut | |
| 700 | 1 | |a Samardzija, Marijana |e verfasserin |4 aut | |
| 700 | 1 | |a Staiano, Leopoldo |e verfasserin |4 aut | |
| 700 | 1 | |a Luciani, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Grimm, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Nussbaum, Robert L |e verfasserin |4 aut | |
| 700 | 1 | |a De Matteis, Maria Antonietta |e verfasserin |4 aut | |
| 700 | 1 | |a Dorchies, Olivier M |e verfasserin |4 aut | |
| 700 | 1 | |a Scapozza, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Wolfer, David Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Devuyst, Olivier |e verfasserin |4 aut | |
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