The Lowe Oculocerebrorenal Syndrome

Human Genome Research

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Abstract

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 the abnormalities in sperm motility and function. We are also determining the cause of the early embryonic lethality in double-deficient mice by X-inactivation mosaicism analysis of tissues in females homozygous for the Inpp5b knock-out and heterozygous for Ocrl1 knock-out. . Ocrl is a golgi protein, located primarily in the trans-Golgi network. We have generated mice carrying conditional knock-out alleles of Inpp5b and Ocrl1. Using mice expressing cre in specific tissues, we are looking to create mice that lack both enzyme activites in a specific tissue, such as proximal tubules of the kidney or the lens of the eye. 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.