The Lowe Oculocerebrorenal Syndrome (OCRL;McK #309000) is an X-linked disorder characterized by mental retardation, congenital cataracts, renal tubular dysfunction in childhood and progressive renal failure in adulthood. We have created mice lacking the OCRL gene (OCRL1) as well as mice lacking the homologous, autosomal phosphatidylinositol (4,5) bisphosphate 5 phosphatase (INPP5B). Both strains of mice are viable and normal phenotypically. In breedings designed to create mice lacking both activities, no liveborn mice are seen lacking both activities. At 9.5 days post coitum, pregnancies have increased numbers of decidua without embryos; none of the embryos seen at that stage are doubly deficient. Thus, we suspect that the double-deficient mice suffer demise early in embryogenesis. In Golgi perturbation assays performed using brefeldin A in cells that either have or lack OCRL1 gene function, it appears that the ocrl1 protein (ocrl1p) behaves as if it were a trans-Golgi network protein. It does not disperse immediately after brefeldin A treatment, the way beta-coatomer does, and is retained at the microtubular organizing center after prolonged treatment with this drug. We have also found three yeast genes with strong homology to the phosphatidylinositol (4,5) bisphosphatase domains of OCRL1 and INPP5B. These three genes have been deleted in yeast and strains of yeast generated lacking single and double knock-outs. All strains have some deficiency in PIP2 phosphatase activity. They have no defects in vacuolar protein sorting but the double knock-out yeast have major abnormalities in vacuole morphology as well as cell membrane morphology. These genes, therefore, appear to be involved in endocytosis, endosome formation, endosome-vacuole fusion, or vacuole stability.
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