OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): 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.