FUNCTIONAL OVERLAP BETWEEN MURINE INPP5B AND OCRL1 MAY EXPLAIN WHY DEFICIENCY OF THE MURINE ORTHOLOG FOR OCRL1 DOES NOT CAUSE LOWE-SYNDROMEIN MICE

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human gen etic disorder characterized by mental retardation, congenital cataract s, and renal tubular dysfunction. The Lowe syndrome gene, OCRL1, encod es a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe syndrome due to deficiency of a phos phatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex i s unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1, the mouse homologue for OCRL1, as an an imal model for the disease. Surprisingly, mice deficient in Ocrl1 do n ot develop the congenital cataracts, renal Fanconi syndrome, or neurol ogical abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-p hosphatase (Inpp5b), an autosomal gene that encodes a phosphatidylinos itol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b; the mice were viable and fertile without ph enotype except for testicular degeneration Ln males beginning after se xual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found , demonstrating that Ocrl1 and Inpp5b have overlapping functions in mi ce and suggesting that the lack of phenotype in Ocrl1-deficient mice m ay be due to compensating Inpp5b function.