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Hum Mol Genet. 2018 Dec 26. doi: 10.1093/hmg/ddy449. [Epub ahead of print]

OCRL Deficiency Impairs Endolysosomal Function in a Humanized Mouse Model for Lowe Syndrome and Dent Disease.

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Institute of Physiology, University of Zurich, CH Zurich, Switzerland.
Division of Functional Neuroanatomy, Institute of Anatomy, University of Zurich, CH Zurich, Switzerland.
Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, ETH Zurich, CH Zurich, Switzerland.
Neuroscience Center Zurich (ZNZ), University of Zurich, CH Zurich, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, CMU, Rue Michel-Servet, Geneva, Switzerland.
Lab for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, CHZurich, Switzerland.
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
Center for Integrative Human Physiology (ZIHP), University of Zurich, CH Zurich, Switzerland.
Department of Medicine and Institute of Human Genetics, University of California, CA San Francisco, California.
Invitae Corporation, CA San Francisco.


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. 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 proximal tubule 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-mechanism and renal phenotypes observed in OcrlY/- and Clcn5 Y/- mice suggest shared mechanisms in Dent disease 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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