OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

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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 loss-of-function 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, an enzyme expressed by all cells of the body, is to dephosphorylate two bilayer phospholipids, PI(4,5)P2 and PI(3,4,5)P3 (members of the phosphoinositide family) at the 5 position of their inositol ring, the mechanisms through which a defect in the catalytic activity of this enzyme cause disease, and specifically kidney disease, remain unclear. The objective of this project is to elucidate such mechanisms. Strong evidence indicates that a main function of OCRL is to avoid accumulation of its substrates on membranes of the endocytic pathway. It is hypothesized that the resulting inappropriate intracellular accumulation of these lipids, primarily PI(4,5)P2, leads to ectopic actn nucleation and abnormal traffic and sorting of membrane proteins along the endocytic pathway. This effect is expected to have a dramatic impact on proximal tubule cells due the massive endocytic activity occurring at their actinrich apical pole. In this proposal we plan to elucidate he physiological function of the intracellular phosphoinositide pools controlled by OCRL, to determine how such pools regulate actin nucleation and endosomal traffic, and to establish how these events specifically affect the function of kidney proximal tubule cells in model mouse and cell lines.