The Lowe Oculocerebrorenal Syndrome (OCRL; McK #309000)m 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 mouse Ocrl gene and the gene for a homologous, autosomal phosphatidylinositol (4,5) bisphosphate 5-phosphatase (inpp5b). Mice deficient in Ocrl are normal; mice deficient in Inpp5b have a phenotype of testicular degeneration associated with vacuolization within the Sertoli cells. Mice deficient in both activities undergo early embryonic death, prior to day 9.5. Studies are ongoing to determine what the nature of the vacuoles in the Inpp5b knock-out mice as well as to determine the cause of the early embryonic lethality in double-deficient mice. Ocrl is a golgi protein. We have generated mice carrying knock-outs of Inpp5b, Ocrl1, and a temperature sensitive SV40 large-T. We are isolating Sertoli cell and renal proximal tubular cell cultures from these mice in order to study the phenotype at the cellular level. Through yeast two-hybrid screens, we have identified a protein that interacts with Ocrl and is itself a type II transmembrane golgi protein. This protein is now being characterized. Additional ESTs have been found that share strong homology with phosphatase domains of Ocrl and Inpp5b. The full- length cDNAs for these genes are being determined and their function studied through cloning in baculovirus.
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