title: Kidney Tubular Ablation ofOcrl/Inpp5bPhenocopies Lowe Syndrome Tubulopathy.
abstract: Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation ofOcrlin mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation ofInpp5bon a globalOcrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia. At the cellular level, we observed a striking impairment of clathrin-dependent and -independent endocytosis in proximal tubules, phenocopying what has been reported for Dent disease caused by mutations in the gene encoding endosomal proton-chloride exchange transporter 5. These results suggest that the functions of OCRL/INPP5B and proton-chloride exchange transporter 5 converge on shared mechanisms, the impairment of which has a dramatic effect on proximal tubule endocytosis.
authors.affiliation: Departments of Internal Medicine.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Cell Biology.|Howard Hughes Medical Institute, and.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Balkin
authors.affiliation: Cell Biology.|Howard Hughes Medical Institute, and.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.|Neuroscience, and.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cell Biology.|Howard Hughes Medical Institute, and.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Nandez
authors.affiliation: Cell Biology.|Howard Hughes Medical Institute, and.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.|Neuroscience, and.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Departments of Internal Medicine.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Tian
authors.affiliation: Cellular and Molecular Physiology.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine and.|Institute of Human Genetics, University of California, San Francisco, California; and.|Howard Hughes Medical Institute, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Nussbaum
authors.affiliation: Cell Biology, pietro.decamilli@yale.edu shuta.ishibe@yale.edu.|Howard Hughes Medical Institute, and.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, Connecticut.|Neuroscience, and.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.affiliation: Departments of Internal Medicine, pietro.decamilli@yale.edu shuta.ishibe@yale.edu.|Cellular and Molecular Physiology.
authors.forename: Shuta
authors.initials: S
authors.lastname: Ishibe
mesh_terms: D000818:Animals; D006801:Humans; D007687:Kidney Tubules, Proximal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C489581:Ocrl protein, mouse
keywords: INPP5B; Lowe syndrome; OCRL; endocytosis; proximal tubulopathy