| Lowe syndrome is a rare x-linked disease whose clinical manifestations include mental retardation, bilateral congenital cataracts and deficits in renal proximal tubule reabsorptive properties (resulting in the renal Fanconi syndrome). In 1992 the gene responsible for Lowe syndrome was identified by positional cloning and named OCRL (OculoCerebroRenal syndrome of Lowe). Recently, it has been shown that Dent's disease, a proximal tubulopathy strikingly similar to the tubulopathy of Lowe syndrome and typically caused by mutations in the chloride channel CLC-5, can also be caused by mutations in OCRL.;OCRL is an inositol 5-phosphatase implicated in membrane and protein trafficking that localizes throughout the endosomal system and the Golgi complex, as well as at late-stage clathrin coated pits and membrane ruffles. The broad intracellular distribution of OCRL is mediated by a diverse cast of intracellular binding partners, including clathrin, clathrin adaptors, small GTPases and endosomal proteins. Intriguingly, the widespread intracellular localization of OCRL contrasts with the predominant localization of its preferred substrates PI(4,5)P2 and PI(3,4,5)P3 at the plasma membrane and at the earliest endocytic stations.;To gain new insight into the function of OCRL in basic cell physiology and human disease, we carried out a proteome-wide assessment of OCRL interacting partners (with Matthias Mann, Miinich) and then used loss of function approaches in cultured cells and mice (with Robert Nussbaum, UCSF) to examine the functional significance of previously described and novel interactions. Our studies suggest a broad action of OCRL on intracellular compartments to couple endocytosis to PI(4,5) P2 and PI(3,4,5)P3 dephosphorylation, to prevent the ectopic accumulation of these phosphoinositides and/or to operate on small yet functionally significant intracellular pools of these phosphoinositides. |
