OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease. (26th December 2018)

• Record Type: Journal Article
• Authors: Festa, Beatrice Paola; Berquez, Marine; Gassama, Alkaly; Amrein, Irmgard; Ismail, Hesham M; Samardzija, Marijana; Staiano, Leopoldo; Luciani, Alessandro; Grimm, Christian; Nussbaum, Robert L; De Matteis, Maria Antonietta; Dorchies, Olivier M; Scapozza, Leonardo; Wolfer, David Paul; Devuyst, Olivier
• Is Part Of: Human molecular genetics. Volume 28:Number 12(2019)
• Page Start: 1931
• Page End: 1946
• Publication Date: 2018-12-26
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy449
• Languages: English
• ISSNs: 0964-6906

Abstract

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 Ocrl Y/− 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 Ocrl Y/− kidneys. The Ocrl Y/− 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 Ocrl Y/− 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 Ocrl Y/− and Clcn5 Y/− 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.