The long-term goal of this proposal is to develop therapeutic strategies for the treatment of two human diseases, Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and Dent disease, which result from mutations in the gene encoding the inositol 5-phosphatase OCRL. Lowe syndrome is a severe X-linked disorder characterized by reabsorption defects in the kidney proximal tubule (renal Fanconi syndrome), mental retardation and congenital cataracts. Dent disease is another X-linked disorder in which the clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. While it is known that the main function of OCRL is to dephosphorylate PI(4,5)P2 and PI(3,4,5)P3 at the 5 position of the inositol ring, the mechanisms through which a defect in this protein causes disease is unclear. The objective of this project is to elucidate these mechanisms in the kidney, as it is the organ consistently affected by mutations in the OCRL gene. Recent studies at the cellular level have suggested that the main site of action of OCRL is the early endocytic pathway, where several major OCRL interactors are concentrated, such as clathrin, the clathrin adaptor AP-2, Rab5 and the endocytic adaptor APPL1. A main working hypothesis is that abnormal levels of PI(4,5)P2, and possibly PI(3,4,5)P3, resulting from impaired OCRL function result in abnormal traffic and sorting of apical plasma membrane proteins in kidney proximal tubule cells. In this proposal we plan to further characterize the molecular properties and interactions of OCRL and of its homologue INPP5B, to elucidate the role of OCRL in endocytic traffic and endosomes dynamics in kidney proximal tubule cells and in model cell lines, to determine the impact of mutations in OCRL/INPP5B on kidney function in mice and to identify proteins whose function enhances or suppresses defects resulting from lack of OCRL. The identification of such modifier genes may provide clues relevant to understanding the impact of different OCRL mutations in Lowe syndrome and Dent disease and toward developing therapies for these conditions. Given the key role of PI metabolism and of the endosomal system in cell physiology and pathology, the results of these studies will be additionally relevant to the elucidation and treatment of a variety of diseases of the kidney as well as other organs.

Public Health Relevance

OculoCerebroRenal Syndrome of Lowe (Lowe Syndrome) is a severe disorder characterized by kidney dysfunction, mental retardation and congenital cataracts, which results from mutations in the gene encoding a lipid metabolizing enzyme called OCRL. Mutations in OCRL can also cause Dent disease, whose clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. The goal of this proposal is to understand how disruption of OCRL function leads to kidney disease with the hope that this information may help to develop therapeutic strategies for these conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Mullins, Christopher V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
Zip Code
Lees, Joshua A; Zhang, Yixiao; Oh, Michael S et al. (2017) Architecture of the human PI4KIII? lipid kinase complex. Proc Natl Acad Sci U S A 114:13720-13725
Lees, Joshua A; Messa, Mirko; Sun, Elizabeth Wen et al. (2017) Lipid transport by TMEM24 at ER-plasma membrane contacts regulates pulsatile insulin secretion. Science 355:
Levin, Roni; Hammond, Gerald R V; Balla, Tamas et al. (2017) Multiphasic dynamics of phosphatidylinositol 4-phosphate during phagocytosis. Mol Biol Cell 28:128-140
Reinisch, Karin M; De Camilli, Pietro (2016) SMP-domain proteins at membrane contact sites: Structure and function. Biochim Biophys Acta 1861:924-927
Saheki, Yasunori; Bian, Xin; Schauder, Curtis M et al. (2016) Control of plasma membrane lipid homeostasis by the extended synaptotagmins. Nat Cell Biol 18:504-15
Baskin, Jeremy M; Wu, Xudong; Christiano, Romain et al. (2016) The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat Cell Biol 18:132-8
Dong, Rui; Saheki, Yasunori; Swarup, Sharan et al. (2016) Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P. Cell 166:408-423
Nakatsu, Fubito; Messa, Mirko; Nández, Ramiro et al. (2015) Sac2/INPP5F is an inositol 4-phosphatase that functions in the endocytic pathway. J Cell Biol 209:85-95
Idevall-Hagren, Olof; Lü, Alice; Xie, Beichen et al. (2015) Triggered Ca2+ influx is required for extended synaptotagmin 1-induced ER-plasma membrane tethering. EMBO J 34:2291-305
Chung, Jeeyun; Torta, Federico; Masai, Kaori et al. (2015) INTRACELLULAR TRANSPORT. PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349:428-32

Showing the most recent 10 out of 34 publications